{"gene":"VCAM1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":1991,"finding":"The human VCAM1 gene is organized into 9 exons spanning ~25 kb, with exons 2–8 encoding C2/H-type immunoglobulin domains. Alternative mRNA splicing that includes or excludes exon 5 generates at least two different VCAM-1 precursor isoforms. The promoter contains NF-κB, GATA family, and AP1 consensus binding sites, and the gene maps to chromosomal region 1p31–32.","method":"Genomic cloning, exon mapping, Southern blot, in situ hybridization, human-mouse hybrid cell line analysis, promoter sequence analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct genomic structural analysis with multiple orthogonal methods (cloning, mapping, hybridization, promoter analysis) in a single rigorous study","pmids":["1715583"],"is_preprint":false},{"year":1993,"finding":"The murine VCAM1 gene contains 10 exons spanning ~20 kb. Alternative splicing of exon 5 generates a truncated three-Ig-domain isoform linked to the membrane via a phosphatidylinositol anchor (encoded by exon 5), distinct from the full-length transmembrane form. The murine core promoter shares conserved NF-κB, Ets, and GATA transcription factor binding sites with the human gene.","method":"Genomic cloning, exon mapping, sequence analysis of promoter and splice junctions","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct structural genomic analysis with sequence-level evidence for alternative splicing and PI-linked isoform","pmids":["7507076"],"is_preprint":false},{"year":1993,"finding":"VCAM-1 is constitutively expressed on murine microvascular endothelium and is strongly upregulated by TNF, IL-1, or LPS (but not PMA or staurosporine). Antibody blocking of VCAM-1 on endothelium or VLA-4 on leukocytes demonstrated that VCAM-1/VLA-4 interaction mediates the adhesion of splenocytes, thymocytes, P815 mastocytoma cells, mast/basophil cells, Molt-4 cells, and eosinophils to cytokine-activated microvascular endothelium.","method":"Flow cytometry, monoclonal antibody blocking adhesion assay, rosette technique","journal":"Cellular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean antibody blocking with multiple cell types, single lab","pmids":["7680963"],"is_preprint":false},{"year":1995,"finding":"VCAM-1/CD106 expressed on TCR-γδ T cell clones undergoes regulated proteolytic shedding by a zinc-activated metalloprotease to generate a soluble 100-kDa form. Phorbol ester increases soluble CD106 release and reduces membrane-bound form; EDTA and 1,10-phenanthroline (metalloprotease inhibitors) specifically block this conversion.","method":"Immunoprecipitation, SDS-PAGE, phorbol ester stimulation, metalloprotease inhibitor experiments","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical characterization with pharmacological inhibitors, single lab, multiple orthogonal approaches","pmids":["7529789"],"is_preprint":false},{"year":1995,"finding":"Both domain 1 and domain 4 of the 7-domain form of VCAM-1 can independently support VLA-4 (α4β1)-mediated monocyte transendothelial migration; antibodies to each domain alone only partially block migration, but their combination fully blocks CD18-independent, VLA-4-mediated migration across CHO-VCAM-1 transfectants and IL-1-activated endothelium.","method":"Domain-specific monoclonal antibody blocking, CHO cell transfection, transendothelial migration assay under chemotactic gradient","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined domain-function mapping with transfected cells and antibody blocking, single lab","pmids":["7545712"],"is_preprint":false},{"year":1997,"finding":"Cross-linking of VCAM-1 on endothelial cells (ECV304) or its counter-receptor VLA-4 on Jurkat T cells activates the phosphoinositide pathway (IP3 production) and triggers a biphasic intracellular Ca2+ mobilization. Cell-cell contact via VLA-4/VCAM-1 interaction induces mutual Ca2+ signaling in both cell types, blocked ~80% by non-cross-linked anti-VLA-4 or anti-VCAM-1 antibodies.","method":"Fura-2 fluorimetry, confocal microscopy, IP3 assay, antibody blocking, co-culture experiments","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical signal transduction assay with multiple readouts (Ca2+, IP3), single lab","pmids":["9209507"],"is_preprint":false},{"year":1997,"finding":"p38 MAP kinase signaling regulates VCAM-1 surface expression at a post-transcriptional level in TNFα-stimulated endothelial cells. The specific p38 inhibitor SB203580 suppressed TNFα-induced VCAM-1 surface expression without affecting VCAM-1 mRNA accumulation, and also blocked MAPKAP kinase-2 activation and Hsp27 phosphorylation. In contrast, ICAM-1 surface expression was unaffected by p38 inhibition.","method":"Kinase activity assay (MAPKAP-K2), phosphorylation assay (Hsp27), flow cytometry for surface expression, Northern blot for mRNA, pharmacological inhibitor (SB203580)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological dissection with mRNA vs. protein readouts, single lab, two orthogonal methods","pmids":["9020057"],"is_preprint":false},{"year":1998,"finding":"Thrombin induces VCAM-1 and ICAM-1 expression on HUVECs via its specific receptor (thrombin receptor-activating peptide mimics the effect; hirudin inhibits it), independent of IL-1 or TNFα signaling. Thrombin-induced VCAM-1 and ICAM-1 were functionally active, supporting monocyte/PBMC adhesion that was blocked by anti-CD18 and anti-CD49d antibodies.","method":"ELISA, RT-PCR, flow cytometry, thrombin receptor-activating peptide, antibody blocking, monocyte adhesion assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor-level dissection with specific peptide agonist and inhibitors, functional adhesion readout, single lab","pmids":["9694714"],"is_preprint":false},{"year":1998,"finding":"IRF-1 (interferon regulatory factor 1) is required for IFN-α and IFN-γ enhancement of TNF-induced VCAM-1 transcription in endothelial cells. IFN treatment increased nuclear IRF-1 levels and IRF-1 binding to the VCAM-1 promoter; transfection of an IRF-1 construct substituted for IFN; and transfection with IRF-2 (a competitive IRF-1 inhibitor) reduced TNF-induced VCAM-1 expression. The primary NF-κB-driven pathway was not affected.","method":"CAT reporter gene assay, EMSA (IRF-1 binding to promoter), Western blot (nuclear IRF-1), transfection of IRF-1 and IRF-2 constructs","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — promoter reporter + EMSA + gain- and loss-of-function transfection, multiple orthogonal methods in one study","pmids":["9625761"],"is_preprint":false},{"year":2000,"finding":"VCAM-1 (CD106) expressed on rheumatoid arthritis synovial fibroblasts (FLS) mediates B cell survival and Bcl-xL upregulation in a contact-dependent manner. Blocking anti-CD106 (but not anti-CD54/ICAM-1) antibodies abolished FLS-induced B cell protection from apoptosis and Bcl-xL induction; cross-linking CD49d/CD29 (VLA-4) on B cells recapitulated the survival signal.","method":"Apoptosis assay (trypan blue, annexin V, propidium iodide, Hoechst), Western blot (Bcl-xL), antibody blocking, VLA-4 cross-linking","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody blocking with multiple apoptosis readouts and VLA-4 cross-linking rescue, single lab","pmids":["10623863"],"is_preprint":false},{"year":2001,"finding":"During G-CSF-induced hematopoietic progenitor cell (HPC) mobilization, neutrophil-derived serine proteases (neutrophil elastase and cathepsin G) cleave VCAM-1 expressed on bone marrow stromal cells, reducing VCAM-1 levels in vivo and thereby contributing to HPC release from the bone marrow niche.","method":"In vivo murine mobilization model, VCAM-1 protein quantification in bone marrow, protease activity assays, identification of neutrophil elastase and cathepsin G as VCAM-1 cleavage enzymes","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model plus direct biochemical identification of cleaving enzymes, single lab","pmids":["11520773"],"is_preprint":false},{"year":2001,"finding":"VCAM-1 plays a dominant role in the initiation of atherosclerosis. Mice with a hypomorphic Vcam1(D4D) allele (2–8% of wild-type VCAM-1 levels) crossed into an LDL-receptor-null background showed significantly reduced early atherosclerotic lesion area compared with wild-type littermates on a cholesterol-enriched diet, while ICAM-1 deficiency alone or combined with VCAM-1 deficiency did not alter nascent lesion formation.","method":"In vivo murine genetic model (hypomorphic Vcam1 allele), en face oil red O aortic staining, lipid and leukocyte profiling","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — controlled in vivo genetic model with paired littermates and quantitative lesion measurement, replicated by independent lesion quantification","pmids":["11375415"],"is_preprint":false},{"year":2001,"finding":"Fibroblast-like synoviocytes (FLS) support B-cell pseudoemperipolesis via co-dependent expression of SDF-1 (chemokine) and CD106 (VCAM-1). SDF-1/CXCR4 signaling was required for B cell chemotaxis beneath FLS, while CD106 engagement of VLA-4 (α4β1/CD49d) was required for firm adhesion/migration; antibodies to CD49d, CD106, or the CS-1 fibronectin peptide inhibited pseudoemperipolesis. Dermal fibroblasts (which express SDF-1 but not CD106) required IL-4-induced CD106 upregulation to support the process.","method":"Antibody blocking assay, pertussis toxin inhibition, cytokine stimulation (IL-4), co-culture migration assay","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual pathway dissection with antibody blocking and gain-of-function cytokine induction, single lab","pmids":["11160154"],"is_preprint":false},{"year":2002,"finding":"VCAM-1 signals through endothelial cells during lymphocyte migration via NADPH oxidase-generated reactive oxygen species (ROS), which subsequently activate matrix metalloproteinases. These signals are required for endothelial cell shape changes that open an 'endothelial cell gate' for leukocyte transmigration, after which endothelial contacts are re-established.","method":"Review synthesizing experimental evidence: NADPH oxidase inhibition, ROS measurement, MMP activation assay, migration assay","journal":"Molecular immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic summary/review paper; original experimental details not fully described in abstract","pmids":["12431382"],"is_preprint":false},{"year":2006,"finding":"Eosinophil adhesion to the module 1–3 region (6d-VCAM-1) is mediated exclusively by α4β1 (CD49d/CD29), whereas adhesion to the module 4–7 region is mediated by both α4β1 and αMβ2 (CD11b/CD18). αMβ2 engagement of module 4 is PI3K-dependent and modulates α4β1-mediated adhesion under flow conditions.","method":"Domain-specific recombinant VCAM-1 constructs, antibody blocking, PI3K inhibitor, leukemic cell lines lacking αMβ2, static and flow adhesion assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted adhesion with domain-specific constructs, pharmacological and genetic dissection, multiple orthogonal methods","pmids":["16943205"],"is_preprint":false},{"year":2008,"finding":"Canonical Wnt/β-catenin signaling negatively regulates VCAM-1 expression on two types of bone marrow cells (stromal and hematopoietic). Wnt3a-mediated VCAM-1 downregulation was blocked by intracellular (Axin) or extracellular (Dkk-1) Wnt inhibitors. LPS restored VCAM-1 expression in Wnt3a-treated cells, indicating functional cross-talk between Wnt and TLR4 pathways.","method":"Recombinant Wnt ligands, retroviral Wnt transduction, Wnt-secreting co-culture, flow cytometry, Axin and Dkk-1 pathway inhibitors, in vivo transplantation","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple gain- and loss-of-function approaches in the same pathway, single lab","pmids":["18951693"],"is_preprint":false},{"year":2012,"finding":"Nuclear-localized FAK regulates VCAM-1 expression via two mechanisms: (1) kinase-active FAK facilitates TNFα-induced MAPK signaling and maintains GATA4, a transcription factor required for VCAM-1 production; (2) kinase-inhibited FAK translocates to the nucleus where its FERM domain directly binds GATA4 and promotes CHIP E3 ligase-dependent GATA4 polyubiquitination and degradation, thereby suppressing VCAM-1 expression. FAK inhibition prevented TNFα-induced VCAM-1 expression in endothelial cells in vivo and during development.","method":"FAK pharmacological inhibition, genetic FAK knockout, nuclear fractionation, direct binding assay (FAK-FERM to GATA4), ubiquitination assay, in vivo heart vessel-associated endothelial cell experiments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct binding assay + ubiquitination mechanism + in vivo genetic and pharmacological validation, multiple orthogonal methods","pmids":["22734001"],"is_preprint":false},{"year":2012,"finding":"IRF-1 and miR-126 reciprocally regulate VCAM-1 expression in endothelial cells in response to triglyceride-rich lipoproteins (TGRL). Proatherogenic TGRL increases IRF-1 expression/activity and decreases miR-126, enhancing VCAM-1; antiatherogenic TGRL does the opposite. Overexpression or silencing of IRF-1 or miR-126 recapitulates proatherogenic or antiatherogenic VCAM-1 regulation.","method":"Gene overexpression and siRNA knockdown, IRF-1 activity assay, miR-126 expression analysis, VCAM-1 protein/mRNA assay, monocyte adhesion assay","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain- and loss-of-function for two regulators, single lab","pmids":["22874466"],"is_preprint":false},{"year":2015,"finding":"Tumor-derived SPARC induces vascular permeability and cancer cell extravasation through endothelial VCAM1 and downstream p38 MAPK signaling. SPARC deficiency abolished tumor-initiated lung capillary permeability and prevented extravasation; SPARC overexpression enhanced them. Blocking VCAM1 specifically impeded SPARC-induced endothelial permeability and melanoma extravasation.","method":"SPARC knockout/overexpression, anti-VCAM1 blocking antibody, in vivo lung permeability assay, extravasation/metastasis assay, p38 MAPK inhibition, comparative secretome proteomics","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss/gain of function combined with antibody blocking and in vivo readouts, multiple orthogonal methods","pmids":["25925867"],"is_preprint":false},{"year":2015,"finding":"VCAM-1+ red pulp macrophages in the spleen retain hematopoietic stem cells (HSCs) via VCAM-1-mediated adhesion. Nanoparticle-RNAi silencing of M-CSFR blocked splenic macrophage maturation and reduced VCAM-1 expression; depletion of macrophages (CD169-iDTR mice) or specific VCAM-1 silencing in macrophages released HSCs from spleen and reduced leukocytosis/inflammation in myocardial infarction and atherosclerosis models.","method":"Nanoparticle-mediated in vivo RNAi, CD169-iDTR macrophage depletion, flow cytometry, murine MI and atherosclerosis models","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic macrophage depletion plus RNAi-mediated VCAM-1 silencing, functionally validated with HSC retention readout, multiple approaches","pmids":["25800955"],"is_preprint":false},{"year":2016,"finding":"oxLDL-induced VCAM-1 expression and monocyte adhesion in endothelial cells requires FAK-dependent activation of p90 RSK, which in turn activates IKKβ and NF-κB. Inhibiting RSK blocks all downstream NF-κB and VCAM-1 induction. Endothelial-specific kinase-dead FAK transgenic mice show reduced RSK activity, decreased VCAM-1 expression, and reduced macrophage accumulation in early atherosclerosis.","method":"RSK pharmacological inhibition, FAK kinase-dead transgenic mice, NF-κB/IKKβ activity assay, VCAM-1 protein/mRNA, monocyte adhesion assay, in vivo atherosclerosis model","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro pathway dissection plus in vivo transgenic validation, multiple orthogonal methods","pmids":["26906414"],"is_preprint":false},{"year":2017,"finding":"VCAM-1 expressed on radial glial cells (RGCs) during embryonic development is required for the embryonic origin of adult neural stem cells (NSCs). Loss of VCAM1 in embryonic RGCs stimulates premature neuronal differentiation, prevents quiescence of slowly-dividing RGCs, and diminishes postnatal/adult NSC numbers and V-SVZ regeneration. Mechanistically, VCAM1 signals through its intracellular domain to regulate β-catenin signaling in a context-dependent manner.","method":"Conditional Vcam1 knockout mice, lineage tracing, BrdU/EdU pulse-chase, adult NSC quantification, V-SVZ regeneration assay, β-catenin reporter assay","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic KO with lineage tracing and signaling readout, multiple in vivo phenotypic assays","pmids":["28728023"],"is_preprint":false},{"year":2017,"finding":"VCAM-1 synergizes with Notch ligand DLL4 to enhance Notch signaling and progenitor T-cell differentiation from HSPCs in vitro. VCAM-1 additionally promotes an inflammatory transcriptional program in nascent HSPCs. Combined DLL4+VCAM-1 presentation on an engineered surface enhanced downstream progenitor T-cell output ~80-fold compared to DLL4 alone.","method":"Engineered stromal cell-free niche with defined protein presentation, flow cytometry for T-cell differentiation markers, Notch signaling reporter, transcriptional profiling","journal":"Nature methods","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined reconstituted system with signaling and differentiation readouts, single lab","pmids":["28394335"],"is_preprint":false},{"year":2018,"finding":"VCAM-1+ macrophage-like 'usher cells' in the zebrafish caudal haematopoietic tissue (CHT) patrol the inner surface of the venous plexus and interact with HSPCs via ITGA4 (integrin α4)-dependent interactions to direct HSPC retention in homing hotspots.","method":"High-resolution live imaging in zebrafish, cell-labelling system, ITGA4 blocking/genetic experiments, VCAM-1 expression characterization","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — live in vivo imaging with genetic functional validation in zebrafish, direct observation of VCAM-1/ITGA4-dependent interaction","pmids":["30455424"],"is_preprint":false},{"year":2019,"finding":"Brain endothelial VCAM1 mediates the detrimental effects of aged plasma on young brains. Aged mouse hippocampal BECs upregulate VCAM1; plasma from aged humans/mice increases VCAM1 in cultured BECs and young mouse hippocampi. Systemic anti-VCAM1 antibody or genetic Vcam1 ablation in BECs reverses microglial reactivity and cognitive deficits in aged mice and counteracts effects of aged plasma in young mice.","method":"Parabiosis/plasma transfer model, conditional BEC-specific Vcam1 knockout mice, anti-VCAM1 antibody treatment, cognitive testing, microglial activation assays","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic BEC-specific KO plus antibody neutralization, multiple in vivo functional readouts (cognition, microglial activation)","pmids":["31086348"],"is_preprint":false},{"year":2019,"finding":"Phc2, an epigenetic regulator, controls HSPC mobilization from bone marrow by transcriptionally repressing Vcam1 in bone marrow stromal cells via H3K27me3 and H2AK119ub histone modifications. Phc2 genetic ablation causes de-repression of Vcam1, retention of HSPCs, and systemic immunodeficiency; pharmacological inhibition of VCAM-1 in Phc2-deficient mice reverses these symptoms.","method":"Phc2 knockout mice, HSPC mobilization assay, chromatin immunoprecipitation (H3K27me3, H2AK119ub), VCAM-1 pharmacological inhibition rescue experiment","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with chromatin-level mechanistic evidence and pharmacological rescue, multiple orthogonal methods","pmids":["31375680"],"is_preprint":false},{"year":2020,"finding":"TRIM65, an E3 ubiquitin ligase, directly interacts with VCAM-1 protein and promotes its polyubiquitination and proteasomal degradation, limiting the duration and magnitude of VCAM-1-mediated inflammation. TRIM65 and VCAM-1 expression are inversely correlated during TNFα-induced endothelial activation; wild-type but not E3-ligase-dead TRIM65 promotes VCAM-1 ubiquitination; TRIM65 knockdown attenuates VCAM-1 degradation. TRIM65-deficient mice show enhanced LPS-induced pulmonary inflammation.","method":"Co-immunoprecipitation, ubiquitination assay, E3-ligase-dead mutant, siRNA knockdown, TRIM65 KO mice, LPS-induced pulmonary inflammation model","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct interaction demonstrated by Co-IP, ubiquitination confirmed with loss-of-function mutant, in vivo KO phenotype, multiple orthogonal methods","pmids":["31310649"],"is_preprint":false},{"year":2021,"finding":"HDAC1/2 promote VCAM-1 expression by suppressing STAT3 acetylation-dependent DNMT1 recruitment to the GATA6 promoter, thereby preventing hypermethylation of GATA6 CpG regions. HDAC1/2 inhibition (Romidepsin) enhanced STAT3 acetylation, increased DNMT1-STAT3 interaction, hypermethylated the GATA6 promoter, reduced GATA6 and VCAM-1 expression, and decreased monocyte adhesion. Blocking STAT3 acetylation (Lys685Arg mutation) disrupted DNMT1-STAT3 interaction and reversed these effects.","method":"Romidepsin treatment, siRNA knockdown of HDAC1/2, methylation-specific PCR, ChIP (STAT3 binding to GATA6 promoter), STAT3 Lys685Arg point mutation, Apoe-/- mouse atherosclerosis model","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1 / Strong — epigenetic mechanism elucidated by ChIP + methylation PCR + point mutation + in vivo validation, multiple orthogonal methods","pmids":["33859766"],"is_preprint":false},{"year":2021,"finding":"Macrophage VLA4 (CD49d)-endothelial VCAM1 interaction promotes vascular permeability in ovarian cancer ascites. Mechanistically, VCAM1 engagement activates RAC1 and ROS, leading to phosphorylation of PYK2 and VE-cadherin, thereby increasing endothelial paracellular permeability. Downregulation of VLA4 on M2 macrophages reduces RAC1/ROS/p-PYK2/p-VE-cad signaling and enhances barrier function. Targeting VLA4/VCAM1 augmented vascular integrity and abrogated ascites formation in vivo.","method":"VLA4/VCAM1 overexpression and knockdown, RAC1 and ROS assays, p-PYK2/p-VE-cadherin Western blot, in vivo permeability assay, anti-VLA4 antibody treatment, bevacizumab combination","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic cascade defined by gain/loss of function with in vivo validation, multiple signaling readouts","pmids":["33295887"],"is_preprint":false},{"year":2021,"finding":"Membrane-bound SCF (mSCF) and VCAM-1 synergistically regulate HSC morphology and adhesion via PI3K signaling and cytoskeletal reorganization. HSCs cluster mSCF at the HSC-substrate interface and form a polarized morphology with a large protrusion when both mSCF and VCAM-1 are present on a supported lipid bilayer. This synergy dramatically enhances HSC adhesion and promotes nuclear retention of FOXO3a, a key HSC maintenance factor, reducing its loss induced by soluble SCF.","method":"Supported lipid bilayer (SLB) system, live cell imaging, PI3K pharmacological inhibition, cytoskeletal inhibitors, FOXO3a nuclear localization assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted membrane system with defined components, pharmacological dissection of signaling, multiple functional readouts","pmids":["34402812"],"is_preprint":false},{"year":2022,"finding":"VCAM1 on hematopoietic stem cells (HSCs) and leukaemic stem cells (LSCs) functions as a 'don't-eat-me' signal in the context of MHC-I presentation, protecting them from phagocyte-mediated clearance. Mechanistically, VCAM1 'don't-eat-me' activity requires β2-microglobulin-dependent MHC-I presentation on HSCs and paired Ig-like receptor-B (PIR-B) on phagocytes. Vcam1 deletion in the setting of haplotype mismatch leads to HSC clearance by mononuclear phagocytes and impaired haematopoietic recovery. In AML, VCAM1 inhibition or deletion reduces leukaemia burden and extends survival.","method":"Vcam1 conditional knockout, haplotype-mismatched transplantation, MHC-I (β2m) genetic manipulation, PIR-B-expressing phagocyte assays, AML mouse model (VCAM1 inhibition)","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic dissection of immune checkpoint mechanism with multiple in vivo models, receptor-ligand pathway defined","pmids":["35210567"],"is_preprint":false},{"year":2022,"finding":"VCAM-1 and DLL4 synergize to activate Notch signaling in nascent HSPCs and enhance T-cell-competent progenitor output ~80-fold from human PSCs; VCAM1 additionally promotes an inflammatory transcriptional program during the endothelial-to-haematopoietic transition.","method":"Defined serum- and feeder-free PSC differentiation system with DLL4 and VCAM1 proteins, Notch signaling reporter, transcriptional profiling, in vivo thymus colonization assay","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined reconstituted differentiation system with signaling and in vivo readouts, single lab","pmids":["36001668"],"is_preprint":false},{"year":2023,"finding":"IL-33-induced VCAM1 in microglia directs microglial chemotaxis toward amyloid-beta (Aβ) plaques by sensing plaque-associated ApoE. Disrupting the VCAM1-ApoE interaction abolishes microglial Aβ chemotaxis and decreases Aβ clearance. Higher CSF soluble VCAM1 in AD patients correlates with impaired microglial Aβ chemotaxis.","method":"IL-33 stimulation, VCAM1 gain/loss of function in microglia, functional screening for chemotaxis, VCAM1-ApoE interaction blocking, in vivo Aβ clearance assay, human CSF correlation","journal":"Nature aging","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional screening identified VCAM1, interaction blocking validated mechanism, in vivo clearance readout, human translational data","pmids":["37735240"],"is_preprint":false},{"year":2023,"finding":"VCAM-1+ endothelial cell-derived extracellular vesicles (EVs) mediate rapid neutrophil mobilization from the spleen to peripheral blood after myocardial infarction. CRISPR/Cas9-mediated deletion of VCAM-1 from endothelial cells removed the ability of EC-EVs to mobilize splenic neutrophils. VCAM-1+ EVs accumulate in the spleen and induce local inflammatory gene/chemokine expression.","method":"CRISPR/Cas9 VCAM-1 KO in parent endothelial cells, EV isolation/characterization, in vivo EV administration, splenic neutrophil mobilization assay, gene expression profiling","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR-mediated deletion with functional in vivo readout, direct demonstration of VCAM-1-dependent EV function","pmids":["35134856"],"is_preprint":false},{"year":2024,"finding":"In the AKI-to-CKD transition, proinflammatory cytokines (TNF-α and IL-1β) induce VCAM-1 expression in proximal tubule cells via NF-κB signaling (requiring MyD88/TRIF adaptors). TNF-α stimulation or VCAM-1 overexpression increases CD45+ splenocyte adhesion to tubular monolayers; NF-κB inhibition or Vcam1 genetic deletion suppresses TNF-α-induced splenocyte adhesion, demonstrating a proximal tubule-immune cell cross-talk role for VCAM-1.","method":"TNF-α/IL-1β stimulation of primary renal cells, NF-κB pharmacological inhibition, MyD88/TRIF genetic deletion, VCAM-1 overexpression, splenocyte adhesion assay, single-cell transcriptomics of patient biopsies","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway dissection with pharmacological and genetic tools, functional adhesion readout, single lab","pmids":["39116349"],"is_preprint":false},{"year":2015,"finding":"VCAM-1 and VAP-1 on tumor-activated pulmonary endothelium recruit myeloid cells that promote tumor cell survival and metastasis. VCAM-1 induction depends on tumor cell-clot formation (blocked by tissue factor pathway inhibitor or hirudin). Anti-VCAM-1 blocking antibody reduces myeloid cell recruitment and tumor cell survival without affecting tumor cell adhesion.","method":"VCAM-1 antibody blocking, tissue factor pathway inhibitor, hirudin treatment, in vivo myeloid cell recruitment assay, tumor survival/metastasis assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody blocking with mechanistic upstream dissection (coagulation dependency) and in vivo metastasis readout, single lab","pmids":["23407548"],"is_preprint":false},{"year":2020,"finding":"CAF-derived VCAM1 (upregulated by H. pylori infection via JAK/STAT1 signaling) molecularly interacts with integrin αvβ1/5 on gastric cancer cells to facilitate tumor invasion. The kinetic binding interaction between VCAM1 and integrin αvβ1/5 was directly measured by biolayer interferometry.","method":"RNA-seq, biolayer interferometry (direct binding kinetics), spheroid invasion assay, zebrafish xenograft model, JAK/STAT1 inhibition","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding kinetics by BLI plus functional invasion assay and in vivo model, single lab","pmids":["32034307"],"is_preprint":false},{"year":2015,"finding":"Endothelial Notch1 intracellular domain (N1ICD) upregulates VCAM1 expression and amplifies IL-1β-mediated VCAM1 induction through a Notch1-Jagged1 autocrine circuit. Forced N1ICD expression upregulated VCAM1 per se; γ-secretase inhibition or Notch1/Jagged1 silencing reduced IL-1β-mediated VCAM1 induction. IL-1β decreases Notch1 mRNA but maintains active N1ICD protein levels.","method":"γ-secretase inhibitor, Notch1/Jagged1 siRNA silencing, N1ICD forced expression, Western blot (Notch1ICD, Jagged1), VCAM1 promoter reporter, liver inflammation model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss of function for Notch1 and Jagged1 with VCAM1 readout, single lab","pmids":["26646450"],"is_preprint":false},{"year":2017,"finding":"FSH promotes endothelial VCAM-1 expression via FSHR located in membrane caveolae interacting with caveolin-1 and GαS, leading to cAMP/PKA elevation and PI3K/Akt/mTOR/NF-κB activation. Disruption of caveolae or caveolin-1 silencing blocks FSH-induced signaling and VCAM-1 expression. FSH increases monocyte adhesion to HUVECs, reversed by VCAM-1 neutralizing antibody.","method":"Luciferase reporter assay, transfection, flow chamber adhesion assay, Western blot, caveolae disruption, caveolin-1 siRNA, PI3K/Akt/mTOR inhibitors, NF-κB luciferase, VCAM-1 neutralizing antibody, ApoE KO atherosclerosis mouse model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-step signaling pathway defined with pharmacological and genetic tools, in vivo validation, single lab","pmids":["29187895"],"is_preprint":false},{"year":2022,"finding":"In MLL-fusion AML, IMPDH inhibition induces overactivation of TLR-TRAF6-NF-κB signaling and upregulation of VCAM1, which contributes to the antileukemia effect. Combined treatment with IMPDH inhibitors and TLR1/2 agonist effectively inhibited MLL-fusion AML development in vivo.","method":"In vitro IMPDH inhibitor treatment, NF-κB signaling assay, VCAM1 expression analysis, in vivo AML mouse model, TLR1/2 agonist combination","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — signaling pathway identified with in vivo functional validation, single lab","pmids":["36453131"],"is_preprint":false},{"year":2019,"finding":"VCAM1 expression in ovarian theca and stromal cells is induced by androgen receptor (AR) signaling; AR antagonist flutamide markedly reduces VCAM1 mRNA and protein in PCOS-derived theca cells. VCAM1 expression is specifically elevated in NR2F2/COUPTF-II lineage theca cells, not granulosa cells, of DHT-treated mice. LH (equine chorionic gonadotropin) transiently induces VCAM1, while hCG (superovulatory dose) potently suppresses it.","method":"Genome-wide microarray, DHT-treatment mouse model, AR antagonist (flutamide) treatment, immunohistochemistry, RT-PCR, PCOS-derived human theca cell culture","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological AR antagonism and in vivo DHT model, single lab","pmids":["30951142"],"is_preprint":false},{"year":2014,"finding":"VCAM1 on the uterine endometrial epithelium and trophoblast ITGA4 (integrin α4) mediate bovine conceptus adhesion to the uterine endometrium during implantation. VCAM1 and ITGA4 expression are mutually upregulated by co-culture of endometrial epithelial cells (EECs) with bovine trophoblast CT1 cells and by uterine flushings. ITGA4 protein is localized specifically to trophoblasts in day-22 pregnant uteri.","method":"Co-culture of EEC and CT1 trophoblast cells, immunohistochemistry (VCAM1, ITGA4 localization), RT-PCR, Western blot, uterine flushing treatment","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-culture system with localization and expression readouts, single lab","pmids":["24803492"],"is_preprint":false},{"year":2022,"finding":"In AML driven by IRF7 loss, VCAM1 is upregulated (correlated with elevated LSC levels), and VCAM1-VLA-4 axis mediates intracerebral invasion of AML cells. Blocking the VCAM1-VLA-4 axis delayed disease progression and attenuated intracerebral invasion in IRF7-/- AML mouse models.","method":"IRF7 KO and overexpression in MLL-AF9 AML model, xenograft mouse model, VCAM1 expression analysis, anti-VCAM1/anti-VLA-4 antibody blocking, intracranial invasion assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic AML model with antibody blocking and in vivo invasion readout, single lab","pmids":["35256780"],"is_preprint":false},{"year":2022,"finding":"Notch1-c-myc-VCAM1 signaling axis drives macrophage-dependent HCC transendothelial migration and pulmonary metastasis. Elevated Notch1 increases c-myc, which transcriptionally upregulates VCAM1. Silencing c-myc prohibits tumorigenicity; VCAM1 depletion reduces spontaneous lung metastasis without affecting primary tumor growth. Macrophage depletion or blockade of macrophage α4β1-integrin (VCAM1 receptor) reduces lung nodule formation.","method":"N1ICD overexpression in LPC, c-myc and VCAM1 siRNA/shRNA, orthotopic rat liver tumor model, macrophage depletion, α4β1 integrin blocking antibody, experimental metastasis model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptional pathway defined with gain/loss of function, macrophage-dependent mechanism validated in vivo, single lab","pmids":["35256782"],"is_preprint":false},{"year":2021,"finding":"NF-κB regulates CD106 (VCAM1) expression in bone marrow mesenchymal stem cells, and CD106 supports hematopoiesis. CD106+ MSCs show increased in vitro capillary tube-like formation, vasculogenesis, and in vivo engraftment of CD34+ cells compared to CD106- MSCs. TNF-α and LPS stimulation of MSCs confirms NF-κB-mediated induction of VCAM1.","method":"Flow cytometry, Illumina HiSeq sequencing, qRT-PCR, Western blot, NF-κB inhibition (blockade assay, immunofluorescence), CD34+ cell engraftment in NOD/SCID mice, colony-forming assays","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — NF-κB pathway confirmed by blockade with functional engraftment readout, single lab","pmids":["28764810"],"is_preprint":false}],"current_model":"VCAM1 is a transmembrane immunoglobulin superfamily glycoprotein expressed on activated endothelial cells, stromal cells, and select progenitor populations; it binds α4β1 (VLA-4/CD49d) and αMβ2 integrins through its Ig domains 1 and 4, mediating leukocyte and stem cell adhesion/migration, while its intracellular domain signals via β-catenin, NADPH oxidase/ROS, and p38 MAPK pathways; its expression is transcriptionally controlled by NF-κB, IRF-1, GATA4/GATA6, Notch1-Jagged1, and Wnt/β-catenin, and post-translationally regulated by TRIM65 E3 ligase-mediated ubiquitination/degradation and metalloprotease-dependent ectodomain shedding to soluble sVCAM-1."},"narrative":{"mechanistic_narrative":"VCAM1 is a transmembrane immunoglobulin-superfamily adhesion glycoprotein expressed on cytokine-activated endothelium, bone marrow and splenic stroma, and select progenitor and macrophage populations, where it governs leukocyte and stem-cell adhesion, migration, and retention across immune, vascular, hematopoietic, and neural contexts [PMID:7680963, PMID:11375415, PMID:25800955]. Its extracellular Ig modules engage integrin counter-receptors with domain specificity: domains 1 and 4 each independently support α4β1 (VLA-4)-mediated leukocyte transendothelial migration, while the module 4–7 region additionally binds αMβ2 in a PI3K-dependent manner [PMID:7545712, PMID:16943205]. Beyond passive tethering, VCAM-1 ligation is a bidirectional signaling event — cross-linking activates phosphoinositide/Ca2+ flux and drives NADPH-oxidase-derived ROS and RAC1 signaling that phosphorylates VE-cadherin to open endothelial junctions for transmigration and to increase vascular permeability [PMID:9209507, PMID:33295887]. The gene is transcriptionally induced by NF-κB downstream of TNF, IL-1, LPS, and thrombin, amplified by IRF-1, Notch1–Jagged1, GATA factors, and HDAC1/2–GATA6 circuits, and repressed by Wnt/β-catenin and Polycomb (Phc2)-mediated H3K27me3/H2AK119ub [PMID:7680963, PMID:9694714, PMID:9625761, PMID:22734001, PMID:33859766, PMID:26646450, PMID:18951693, PMID:31375680]. Surface levels are further set post-transcriptionally by p38 MAPK and post-translationally by TRIM65 E3-ligase-mediated polyubiquitination/degradation and by metalloprotease- and neutrophil-protease-dependent ectodomain shedding that releases soluble VCAM-1 [PMID:9020057, PMID:31310649, PMID:7529789, PMID:11520773]. Functionally, VCAM-1 is a dominant initiator of atherosclerotic lesion formation, retains hematopoietic and neural stem cells in their niches, acts via its intracellular domain on β-catenin to specify adult neural stem cells, mediates aged-plasma-driven cognitive decline through brain endothelium, directs microglial chemotaxis to amyloid-β by sensing ApoE, and serves as a β2-microglobulin/MHC-I-dependent 'don't-eat-me' signal protecting hematopoietic and leukemic stem cells from PIR-B-bearing phagocytes [PMID:11375415, PMID:25800955, PMID:28728023, PMID:31086348, PMID:37735240, PMID:35210567].","teleology":[{"year":1991,"claim":"Establishing the genomic architecture and promoter of VCAM1 defined how the gene is regulated and how isoform diversity arises, anchoring all later regulatory studies.","evidence":"Genomic cloning, exon mapping, and promoter sequence analysis of the human (and later murine) gene","pmids":["1715583","7507076"],"confidence":"High","gaps":["Functional consequences of exon-5 alternative splicing and the PI-anchored isoform not resolved","Promoter elements identified by sequence but not yet functionally dissected"]},{"year":1993,"claim":"Demonstrating cytokine-inducible VCAM-1 mediating VLA-4-dependent leukocyte adhesion to endothelium established its core role as an inflammatory adhesion receptor.","evidence":"Flow cytometry and monoclonal antibody blocking adhesion assays on cytokine-activated murine microvascular endothelium","pmids":["7680963"],"confidence":"Medium","gaps":["Did not map which Ig domains mediate binding","Single-lab antibody-based evidence"]},{"year":1995,"claim":"Mapping adhesion to Ig domains 1 and 4 and showing regulated metalloprotease shedding defined both the ligand-binding architecture and a mechanism for generating soluble VCAM-1.","evidence":"Domain-specific antibody blocking with CHO transfectants in transmigration assays; immunoprecipitation with metalloprotease inhibitors for shedding","pmids":["7545712","7529789"],"confidence":"Medium","gaps":["Identity of the physiological sheddase not defined","Function of soluble VCAM-1 not addressed"]},{"year":1997,"claim":"Showing that VCAM-1 cross-linking triggers phosphoinositide/Ca2+ signaling and that p38 MAPK controls surface expression post-transcriptionally established VCAM-1 as a bidirectional signaling molecule, not merely a static ligand.","evidence":"Fura-2/IP3 assays with antibody cross-linking; p38 inhibitor (SB203580) with mRNA vs surface-protein readouts in TNFα-stimulated endothelium","pmids":["9209507","9020057"],"confidence":"Medium","gaps":["Intracellular effectors linking cross-linking to Ca2+ not identified","p38 target controlling surface trafficking unknown"]},{"year":1998,"claim":"Defining IRF-1 as required for IFN amplification of TNF-induced transcription and thrombin as an NF-κB-independent inducer expanded the upstream regulatory network beyond canonical cytokines.","evidence":"CAT reporter, EMSA, and IRF-1/IRF-2 transfection; thrombin receptor peptide and hirudin with adhesion readouts on HUVECs","pmids":["9625761","9694714"],"confidence":"High","gaps":["Combinatorial logic between IRF-1 and NF-κB at the promoter not fully resolved"]},{"year":2001,"claim":"Genetic hypomorph studies showing VCAM-1 (not ICAM-1) dominates atherosclerosis initiation, plus protease cleavage during HPC mobilization, established VCAM-1 as a causal driver of disease and a regulated niche-retention molecule.","evidence":"Hypomorphic Vcam1(D4D) allele in LDLR-null mice with en face lesion quantification; in vivo G-CSF mobilization with neutrophil elastase/cathepsin G cleavage","pmids":["11375415","11520773"],"confidence":"High","gaps":["Cell-type-specific contributions to lesion initiation not dissected","Whether shedding is cause or consequence of mobilization unclear"]},{"year":2006,"claim":"Reconstituting eosinophil adhesion with domain-specific constructs confirmed dual integrin usage — α4β1 across the molecule and αMβ2 on module 4 in a PI3K-dependent, flow-modulated manner — refining the ligand map.","evidence":"Recombinant domain constructs, antibody blocking, PI3K inhibitor, and αMβ2-null cell lines under static and flow adhesion","pmids":["16943205"],"confidence":"High","gaps":["Structural basis of αMβ2 module-4 binding not defined"]},{"year":2012,"claim":"Identifying nuclear FAK–GATA4/CHIP control and reciprocal IRF-1/miR-126 regulation revealed that VCAM-1 transcription is gated at the transcription-factor stability and microRNA levels under inflammatory and lipoprotein stimuli.","evidence":"FAK genetic/pharmacological perturbation with FERM–GATA4 binding and ubiquitination assays; IRF-1 and miR-126 gain/loss of function with TGRL stimulation","pmids":["22734001","22874466"],"confidence":"High","gaps":["Integration of FAK/GATA4 axis with NF-κB and IRF-1 inputs not unified","miR-126 direct target sites on VCAM1 not mapped"]},{"year":2015,"claim":"Showing tumor SPARC and pulmonary endothelial VCAM-1/VAP-1 promote permeability, myeloid recruitment, and metastasis, and that splenic VCAM-1+ macrophages retain HSCs, broadened VCAM-1 function into cancer dissemination and stem-cell niche control.","evidence":"SPARC knockout/overexpression with anti-VCAM1 blocking and in vivo permeability/extravasation; coagulation-dependent VCAM-1 induction; nanoparticle-RNAi and CD169-iDTR macrophage depletion with HSC retention readouts","pmids":["25925867","23407548","25800955"],"confidence":"High","gaps":["How VCAM-1 signaling distinguishes adhesion from permeability outputs not resolved","Upstream signal coupling SPARC to endothelial VCAM-1 p38 not fully traced"]},{"year":2017,"claim":"Conditional knockout in radial glia demonstrated a developmental, cell-intrinsic role for VCAM-1 acting through its intracellular domain on β-catenin to establish adult neural stem cells, plus a synthetic role synergizing with DLL4/Notch in HSPC and T-cell progenitor specification.","evidence":"Conditional Vcam1 knockout with lineage tracing and β-catenin reporters; engineered DLL4+VCAM-1 surfaces with Notch reporters and T-progenitor output","pmids":["28728023","28394335"],"confidence":"High","gaps":["Identity of intracellular-domain effectors coupling to β-catenin not defined","Whether Notch synergy requires VCAM-1 signaling or only co-presentation unclear"]},{"year":2019,"claim":"Establishing brain endothelial VCAM-1 as the mediator of aged-plasma effects on cognition, and Polycomb (Phc2) repression of stromal Vcam1 controlling HSPC mobilization, linked VCAM-1 to aging neuroinflammation and epigenetically gated hematopoiesis.","evidence":"BEC-specific Vcam1 KO and anti-VCAM1 antibody with cognitive/microglial readouts; Phc2 KO with H3K27me3/H2AK119ub ChIP and VCAM-1 inhibition rescue","pmids":["31086348","31375680"],"confidence":"High","gaps":["Plasma factor inducing endothelial VCAM-1 in aging not identified","Whether VCAM-1 signals into BECs or recruits leukocytes to cause cognitive deficit not separated"]},{"year":2020,"claim":"Identifying TRIM65 as a direct E3 ligase driving VCAM-1 polyubiquitination/degradation defined a post-translational brake limiting inflammation duration.","evidence":"Co-IP, ubiquitination assays with E3-dead mutant, siRNA, and TRIM65 KO mice in LPS pulmonary inflammation","pmids":["31310649"],"confidence":"High","gaps":["Lysine residues targeted on VCAM-1 not mapped","Signals that activate TRIM65 toward VCAM-1 unknown"]},{"year":2021,"claim":"Mechanistic dissection of VCAM-1 outside-in signaling (RAC1/ROS/PYK2/VE-cadherin), epigenetic HDAC1/2–STAT3–DNMT1–GATA6 control, and SCF/PI3K synergy maintaining FOXO3a clarified how VCAM-1 simultaneously regulates permeability, its own transcription, and stem-cell maintenance.","evidence":"VLA4/VCAM1 gain/loss with RAC1/ROS and p-PYK2/p-VE-cad readouts in ovarian ascites; Romidepsin/HDAC siRNA with methylation PCR and STAT3 K685R; supported lipid bilayer with PI3K inhibition and FOXO3a localization","pmids":["33295887","33859766","34402812"],"confidence":"High","gaps":["Direct intracellular VCAM-1 binding partners transmitting RAC1 signal not identified","How membrane-bound SCF and VCAM-1 co-cluster mechanistically unresolved"]},{"year":2022,"claim":"Defining VCAM-1 as a β2m/MHC-I-dependent 'don't-eat-me' signal engaging phagocyte PIR-B, and as a Notch/c-myc-driven mediator of leukemic and HCC dissemination, repositioned VCAM-1 as an immune checkpoint and metastasis effector with therapeutic implications.","evidence":"Vcam1 conditional KO with haplotype-mismatched transplant, β2m manipulation, and PIR-B phagocyte assays; AML/HCC models with Notch1-c-myc-VCAM1 axis and α4β1 blockade","pmids":["35210567","35256780","35256782","36453131"],"confidence":"High","gaps":["Structural basis of VCAM-1/PIR-B engagement vs integrin binding not resolved","Whether VCAM-1 checkpoint and adhesion functions are separable not addressed"]},{"year":2023,"claim":"Showing IL-33-induced microglial VCAM-1 senses plaque ApoE to direct chemotaxis and Aβ clearance, and that VCAM-1+ endothelial EVs mobilize splenic neutrophils after MI, revealed cell-autonomous and vesicle-mediated VCAM-1 functions beyond endothelial adhesion.","evidence":"VCAM1 gain/loss in microglia with VCAM1-ApoE interaction blocking and Aβ clearance, plus human CSF correlation; CRISPR VCAM-1 KO in EC-EVs with in vivo neutrophil mobilization","pmids":["37735240","35134856"],"confidence":"High","gaps":["Whether VCAM1-ApoE binding is direct and its structural interface unknown","How VCAM-1 on EVs signals to splenic targets not defined"]},{"year":2024,"claim":"Demonstrating NF-κB/MyD88/TRIF-dependent VCAM-1 induction in proximal tubule cells driving immune-cell adhesion extended the inflammatory-adhesion paradigm to the AKI-to-CKD transition.","evidence":"TNF-α/IL-1β stimulation of primary renal cells with NF-κB inhibition, MyD88/TRIF deletion, VCAM-1 overexpression, and splenocyte adhesion assays plus patient single-cell data","pmids":["39116349"],"confidence":"Medium","gaps":["Single-lab functional data","In vivo causal contribution of tubular VCAM-1 to fibrosis not established"]},{"year":null,"claim":"The intracellular domain effectors that couple VCAM-1 ligation to β-catenin, RAC1/ROS, and Ca2+ signaling remain unidentified, and the structural distinction between its integrin-binding, ApoE-sensing, and PIR-B checkpoint functions is unresolved.","evidence":"No direct cytoplasmic-tail interactor or structural study in the timeline","pmids":[],"confidence":"Low","gaps":["No defined cytoplasmic-domain binding partner","No structural model of the multiple ligand interfaces","Whether adhesion, signaling, and checkpoint functions are separable not tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2,4,14,23,41]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5,28,21]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[32]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3,4,14]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,32]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,4,14,34]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[11,18,24,30,42]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,20,28]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[21,23,41]}],"complexes":[],"partners":["ITGA4","ITGB1","ITGAM","ITGB2","TRIM65","ITGAV","APOE"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P19320","full_name":"Vascular cell adhesion protein 1","aliases":["INCAM-100"],"length_aa":739,"mass_kda":81.3,"function":"Cell adhesion glycoprotein predominantly expressed on the surface of endothelial cells that plays an important role in immune surveillance and inflammation (PubMed:31310649). Acts as a major regulator of leukocyte adhesion to the endothelium through interaction with different types of integrins (PubMed:10209034). During inflammatory responses, binds ligands on the surface of activated endothelial cells to initiate the activation of calcium channels and the plasma membrane-associated small GTPase RAC1 leading to leukocyte transendothelial migration (PubMed:22970700). Also serves as a quality-control checkpoint for entry into bone marrow by providing a 'don't-eat-me' stamping in the context of major histocompatibility complex (MHC) class-I presentation (PubMed:35210567)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P19320/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/VCAM1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/VCAM1","total_profiled":1310},"omim":[{"mim_id":"620579","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 3; CCDC3","url":"https://www.omim.org/entry/620579"},{"mim_id":"619642","title":"TRANSMEMBRANE p24 TRAFFICKING PROTEIN 2; TMED2","url":"https://www.omim.org/entry/619642"},{"mim_id":"617462","title":"PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA, COACTIVATOR-RELATED PROTEIN 1; PPRC1","url":"https://www.omim.org/entry/617462"},{"mim_id":"611767","title":"MICRO RNA 126; MIR126","url":"https://www.omim.org/entry/611767"},{"mim_id":"608272","title":"NEURAMINIDASE 1; NEU1","url":"https://www.omim.org/entry/608272"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cell Junctions","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":366.8}],"url":"https://www.proteinatlas.org/search/VCAM1"},"hgnc":{"alias_symbol":["CD106"],"prev_symbol":[]},"alphafold":{"accession":"P19320","domains":[{"cath_id":"2.60.40.10","chopping":"27-114","consensus_level":"high","plddt":90.7343,"start":27,"end":114},{"cath_id":"2.60.40.10","chopping":"121-218","consensus_level":"medium","plddt":87.4664,"start":121,"end":218},{"cath_id":"2.60.40.10","chopping":"222-310","consensus_level":"medium","plddt":91.0194,"start":222,"end":310},{"cath_id":"2.60.40.10","chopping":"315-402","consensus_level":"medium","plddt":90.4103,"start":315,"end":402},{"cath_id":"2.60.40.10","chopping":"409-506","consensus_level":"medium","plddt":85.5996,"start":409,"end":506},{"cath_id":"2.60.40.10","chopping":"510-598","consensus_level":"medium","plddt":91.2902,"start":510,"end":598},{"cath_id":"2.60.40.10","chopping":"604-687","consensus_level":"high","plddt":86.6483,"start":604,"end":687}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P19320","model_url":"https://alphafold.ebi.ac.uk/files/AF-P19320-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P19320-F1-predicted_aligned_error_v6.png","plddt_mean":84.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=VCAM1","jax_strain_url":"https://www.jax.org/strain/search?query=VCAM1"},"sequence":{"accession":"P19320","fasta_url":"https://rest.uniprot.org/uniprotkb/P19320.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P19320/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P19320"}},"corpus_meta":[{"pmid":"11375415","id":"PMC_11375415","title":"A major role for VCAM-1, but not ICAM-1, in early atherosclerosis.","date":"2001","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/11375415","citation_count":955,"is_preprint":false},{"pmid":"11520773","id":"PMC_11520773","title":"Vascular cell adhesion molecule-1 (CD106) is cleaved by neutrophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor.","date":"2001","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11520773","citation_count":373,"is_preprint":false},{"pmid":"31086348","id":"PMC_31086348","title":"Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1.","date":"2019","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31086348","citation_count":345,"is_preprint":false},{"pmid":"37442359","id":"PMC_37442359","title":"ICAM-1 and VCAM-1: Gatekeepers in various inflammatory and cardiovascular disorders.","date":"2023","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37442359","citation_count":297,"is_preprint":false},{"pmid":"7689792","id":"PMC_7689792","title":"Expression of VCAM-1 and E-selectin in an in vivo model of endothelial activation.","date":"1993","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/7689792","citation_count":211,"is_preprint":false},{"pmid":"7543921","id":"PMC_7543921","title":"Ligation of CD40 on fibroblasts induces CD54 (ICAM-1) and CD106 (VCAM-1) up-regulation and IL-6 production and proliferation.","date":"1995","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/7543921","citation_count":201,"is_preprint":false},{"pmid":"1715583","id":"PMC_1715583","title":"Gene structure, chromosomal location, and basis for alternative mRNA splicing of the human VCAM1 gene.","date":"1991","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1715583","citation_count":191,"is_preprint":false},{"pmid":"34000374","id":"PMC_34000374","title":"VCAM-1 as a predictor biomarker in cardiovascular disease.","date":"2021","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/34000374","citation_count":180,"is_preprint":false},{"pmid":"9020057","id":"PMC_9020057","title":"p38 mitogen activated protein kinase regulates endothelial VCAM-1 expression at the post-transcriptional level.","date":"1997","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9020057","citation_count":178,"is_preprint":false},{"pmid":"23555021","id":"PMC_23555021","title":"CD106 identifies a subpopulation of mesenchymal stem cells with unique immunomodulatory properties.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23555021","citation_count":173,"is_preprint":false},{"pmid":"9694714","id":"PMC_9694714","title":"Thrombin-activated human endothelial cells support monocyte adhesion in vitro following expression of intercellular adhesion molecule-1 (ICAM-1; CD54) and vascular cell adhesion molecule-1 (VCAM-1; CD106).","date":"1998","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9694714","citation_count":172,"is_preprint":false},{"pmid":"25925867","id":"PMC_25925867","title":"Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25925867","citation_count":162,"is_preprint":false},{"pmid":"22461363","id":"PMC_22461363","title":"Nanobodies targeting mouse/human VCAM1 for the nuclear imaging of atherosclerotic lesions.","date":"2012","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/22461363","citation_count":156,"is_preprint":false},{"pmid":"11160154","id":"PMC_11160154","title":"Fibroblast-like synoviocytes support B-cell pseudoemperipolesis via a stromal cell-derived factor-1- and CD106 (VCAM-1)-dependent mechanism.","date":"2001","source":"The Journal of clinical 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Alternative mRNA splicing that includes or excludes exon 5 generates at least two different VCAM-1 precursor isoforms. The promoter contains NF-κB, GATA family, and AP1 consensus binding sites, and the gene maps to chromosomal region 1p31–32.\",\n      \"method\": \"Genomic cloning, exon mapping, Southern blot, in situ hybridization, human-mouse hybrid cell line analysis, promoter sequence analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct genomic structural analysis with multiple orthogonal methods (cloning, mapping, hybridization, promoter analysis) in a single rigorous study\",\n      \"pmids\": [\"1715583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The murine VCAM1 gene contains 10 exons spanning ~20 kb. Alternative splicing of exon 5 generates a truncated three-Ig-domain isoform linked to the membrane via a phosphatidylinositol anchor (encoded by exon 5), distinct from the full-length transmembrane form. The murine core promoter shares conserved NF-κB, Ets, and GATA transcription factor binding sites with the human gene.\",\n      \"method\": \"Genomic cloning, exon mapping, sequence analysis of promoter and splice junctions\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct structural genomic analysis with sequence-level evidence for alternative splicing and PI-linked isoform\",\n      \"pmids\": [\"7507076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"VCAM-1 is constitutively expressed on murine microvascular endothelium and is strongly upregulated by TNF, IL-1, or LPS (but not PMA or staurosporine). Antibody blocking of VCAM-1 on endothelium or VLA-4 on leukocytes demonstrated that VCAM-1/VLA-4 interaction mediates the adhesion of splenocytes, thymocytes, P815 mastocytoma cells, mast/basophil cells, Molt-4 cells, and eosinophils to cytokine-activated microvascular endothelium.\",\n      \"method\": \"Flow cytometry, monoclonal antibody blocking adhesion assay, rosette technique\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean antibody blocking with multiple cell types, single lab\",\n      \"pmids\": [\"7680963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"VCAM-1/CD106 expressed on TCR-γδ T cell clones undergoes regulated proteolytic shedding by a zinc-activated metalloprotease to generate a soluble 100-kDa form. Phorbol ester increases soluble CD106 release and reduces membrane-bound form; EDTA and 1,10-phenanthroline (metalloprotease inhibitors) specifically block this conversion.\",\n      \"method\": \"Immunoprecipitation, SDS-PAGE, phorbol ester stimulation, metalloprotease inhibitor experiments\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical characterization with pharmacological inhibitors, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"7529789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Both domain 1 and domain 4 of the 7-domain form of VCAM-1 can independently support VLA-4 (α4β1)-mediated monocyte transendothelial migration; antibodies to each domain alone only partially block migration, but their combination fully blocks CD18-independent, VLA-4-mediated migration across CHO-VCAM-1 transfectants and IL-1-activated endothelium.\",\n      \"method\": \"Domain-specific monoclonal antibody blocking, CHO cell transfection, transendothelial migration assay under chemotactic gradient\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined domain-function mapping with transfected cells and antibody blocking, single lab\",\n      \"pmids\": [\"7545712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Cross-linking of VCAM-1 on endothelial cells (ECV304) or its counter-receptor VLA-4 on Jurkat T cells activates the phosphoinositide pathway (IP3 production) and triggers a biphasic intracellular Ca2+ mobilization. Cell-cell contact via VLA-4/VCAM-1 interaction induces mutual Ca2+ signaling in both cell types, blocked ~80% by non-cross-linked anti-VLA-4 or anti-VCAM-1 antibodies.\",\n      \"method\": \"Fura-2 fluorimetry, confocal microscopy, IP3 assay, antibody blocking, co-culture experiments\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical signal transduction assay with multiple readouts (Ca2+, IP3), single lab\",\n      \"pmids\": [\"9209507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"p38 MAP kinase signaling regulates VCAM-1 surface expression at a post-transcriptional level in TNFα-stimulated endothelial cells. The specific p38 inhibitor SB203580 suppressed TNFα-induced VCAM-1 surface expression without affecting VCAM-1 mRNA accumulation, and also blocked MAPKAP kinase-2 activation and Hsp27 phosphorylation. In contrast, ICAM-1 surface expression was unaffected by p38 inhibition.\",\n      \"method\": \"Kinase activity assay (MAPKAP-K2), phosphorylation assay (Hsp27), flow cytometry for surface expression, Northern blot for mRNA, pharmacological inhibitor (SB203580)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological dissection with mRNA vs. protein readouts, single lab, two orthogonal methods\",\n      \"pmids\": [\"9020057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Thrombin induces VCAM-1 and ICAM-1 expression on HUVECs via its specific receptor (thrombin receptor-activating peptide mimics the effect; hirudin inhibits it), independent of IL-1 or TNFα signaling. Thrombin-induced VCAM-1 and ICAM-1 were functionally active, supporting monocyte/PBMC adhesion that was blocked by anti-CD18 and anti-CD49d antibodies.\",\n      \"method\": \"ELISA, RT-PCR, flow cytometry, thrombin receptor-activating peptide, antibody blocking, monocyte adhesion assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor-level dissection with specific peptide agonist and inhibitors, functional adhesion readout, single lab\",\n      \"pmids\": [\"9694714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"IRF-1 (interferon regulatory factor 1) is required for IFN-α and IFN-γ enhancement of TNF-induced VCAM-1 transcription in endothelial cells. IFN treatment increased nuclear IRF-1 levels and IRF-1 binding to the VCAM-1 promoter; transfection of an IRF-1 construct substituted for IFN; and transfection with IRF-2 (a competitive IRF-1 inhibitor) reduced TNF-induced VCAM-1 expression. The primary NF-κB-driven pathway was not affected.\",\n      \"method\": \"CAT reporter gene assay, EMSA (IRF-1 binding to promoter), Western blot (nuclear IRF-1), transfection of IRF-1 and IRF-2 constructs\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — promoter reporter + EMSA + gain- and loss-of-function transfection, multiple orthogonal methods in one study\",\n      \"pmids\": [\"9625761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"VCAM-1 (CD106) expressed on rheumatoid arthritis synovial fibroblasts (FLS) mediates B cell survival and Bcl-xL upregulation in a contact-dependent manner. Blocking anti-CD106 (but not anti-CD54/ICAM-1) antibodies abolished FLS-induced B cell protection from apoptosis and Bcl-xL induction; cross-linking CD49d/CD29 (VLA-4) on B cells recapitulated the survival signal.\",\n      \"method\": \"Apoptosis assay (trypan blue, annexin V, propidium iodide, Hoechst), Western blot (Bcl-xL), antibody blocking, VLA-4 cross-linking\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody blocking with multiple apoptosis readouts and VLA-4 cross-linking rescue, single lab\",\n      \"pmids\": [\"10623863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"During G-CSF-induced hematopoietic progenitor cell (HPC) mobilization, neutrophil-derived serine proteases (neutrophil elastase and cathepsin G) cleave VCAM-1 expressed on bone marrow stromal cells, reducing VCAM-1 levels in vivo and thereby contributing to HPC release from the bone marrow niche.\",\n      \"method\": \"In vivo murine mobilization model, VCAM-1 protein quantification in bone marrow, protease activity assays, identification of neutrophil elastase and cathepsin G as VCAM-1 cleavage enzymes\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model plus direct biochemical identification of cleaving enzymes, single lab\",\n      \"pmids\": [\"11520773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"VCAM-1 plays a dominant role in the initiation of atherosclerosis. Mice with a hypomorphic Vcam1(D4D) allele (2–8% of wild-type VCAM-1 levels) crossed into an LDL-receptor-null background showed significantly reduced early atherosclerotic lesion area compared with wild-type littermates on a cholesterol-enriched diet, while ICAM-1 deficiency alone or combined with VCAM-1 deficiency did not alter nascent lesion formation.\",\n      \"method\": \"In vivo murine genetic model (hypomorphic Vcam1 allele), en face oil red O aortic staining, lipid and leukocyte profiling\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — controlled in vivo genetic model with paired littermates and quantitative lesion measurement, replicated by independent lesion quantification\",\n      \"pmids\": [\"11375415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Fibroblast-like synoviocytes (FLS) support B-cell pseudoemperipolesis via co-dependent expression of SDF-1 (chemokine) and CD106 (VCAM-1). SDF-1/CXCR4 signaling was required for B cell chemotaxis beneath FLS, while CD106 engagement of VLA-4 (α4β1/CD49d) was required for firm adhesion/migration; antibodies to CD49d, CD106, or the CS-1 fibronectin peptide inhibited pseudoemperipolesis. Dermal fibroblasts (which express SDF-1 but not CD106) required IL-4-induced CD106 upregulation to support the process.\",\n      \"method\": \"Antibody blocking assay, pertussis toxin inhibition, cytokine stimulation (IL-4), co-culture migration assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual pathway dissection with antibody blocking and gain-of-function cytokine induction, single lab\",\n      \"pmids\": [\"11160154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"VCAM-1 signals through endothelial cells during lymphocyte migration via NADPH oxidase-generated reactive oxygen species (ROS), which subsequently activate matrix metalloproteinases. These signals are required for endothelial cell shape changes that open an 'endothelial cell gate' for leukocyte transmigration, after which endothelial contacts are re-established.\",\n      \"method\": \"Review synthesizing experimental evidence: NADPH oxidase inhibition, ROS measurement, MMP activation assay, migration assay\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic summary/review paper; original experimental details not fully described in abstract\",\n      \"pmids\": [\"12431382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Eosinophil adhesion to the module 1–3 region (6d-VCAM-1) is mediated exclusively by α4β1 (CD49d/CD29), whereas adhesion to the module 4–7 region is mediated by both α4β1 and αMβ2 (CD11b/CD18). αMβ2 engagement of module 4 is PI3K-dependent and modulates α4β1-mediated adhesion under flow conditions.\",\n      \"method\": \"Domain-specific recombinant VCAM-1 constructs, antibody blocking, PI3K inhibitor, leukemic cell lines lacking αMβ2, static and flow adhesion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted adhesion with domain-specific constructs, pharmacological and genetic dissection, multiple orthogonal methods\",\n      \"pmids\": [\"16943205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Canonical Wnt/β-catenin signaling negatively regulates VCAM-1 expression on two types of bone marrow cells (stromal and hematopoietic). Wnt3a-mediated VCAM-1 downregulation was blocked by intracellular (Axin) or extracellular (Dkk-1) Wnt inhibitors. LPS restored VCAM-1 expression in Wnt3a-treated cells, indicating functional cross-talk between Wnt and TLR4 pathways.\",\n      \"method\": \"Recombinant Wnt ligands, retroviral Wnt transduction, Wnt-secreting co-culture, flow cytometry, Axin and Dkk-1 pathway inhibitors, in vivo transplantation\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple gain- and loss-of-function approaches in the same pathway, single lab\",\n      \"pmids\": [\"18951693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nuclear-localized FAK regulates VCAM-1 expression via two mechanisms: (1) kinase-active FAK facilitates TNFα-induced MAPK signaling and maintains GATA4, a transcription factor required for VCAM-1 production; (2) kinase-inhibited FAK translocates to the nucleus where its FERM domain directly binds GATA4 and promotes CHIP E3 ligase-dependent GATA4 polyubiquitination and degradation, thereby suppressing VCAM-1 expression. FAK inhibition prevented TNFα-induced VCAM-1 expression in endothelial cells in vivo and during development.\",\n      \"method\": \"FAK pharmacological inhibition, genetic FAK knockout, nuclear fractionation, direct binding assay (FAK-FERM to GATA4), ubiquitination assay, in vivo heart vessel-associated endothelial cell experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct binding assay + ubiquitination mechanism + in vivo genetic and pharmacological validation, multiple orthogonal methods\",\n      \"pmids\": [\"22734001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IRF-1 and miR-126 reciprocally regulate VCAM-1 expression in endothelial cells in response to triglyceride-rich lipoproteins (TGRL). Proatherogenic TGRL increases IRF-1 expression/activity and decreases miR-126, enhancing VCAM-1; antiatherogenic TGRL does the opposite. Overexpression or silencing of IRF-1 or miR-126 recapitulates proatherogenic or antiatherogenic VCAM-1 regulation.\",\n      \"method\": \"Gene overexpression and siRNA knockdown, IRF-1 activity assay, miR-126 expression analysis, VCAM-1 protein/mRNA assay, monocyte adhesion assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain- and loss-of-function for two regulators, single lab\",\n      \"pmids\": [\"22874466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Tumor-derived SPARC induces vascular permeability and cancer cell extravasation through endothelial VCAM1 and downstream p38 MAPK signaling. SPARC deficiency abolished tumor-initiated lung capillary permeability and prevented extravasation; SPARC overexpression enhanced them. Blocking VCAM1 specifically impeded SPARC-induced endothelial permeability and melanoma extravasation.\",\n      \"method\": \"SPARC knockout/overexpression, anti-VCAM1 blocking antibody, in vivo lung permeability assay, extravasation/metastasis assay, p38 MAPK inhibition, comparative secretome proteomics\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss/gain of function combined with antibody blocking and in vivo readouts, multiple orthogonal methods\",\n      \"pmids\": [\"25925867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"VCAM-1+ red pulp macrophages in the spleen retain hematopoietic stem cells (HSCs) via VCAM-1-mediated adhesion. Nanoparticle-RNAi silencing of M-CSFR blocked splenic macrophage maturation and reduced VCAM-1 expression; depletion of macrophages (CD169-iDTR mice) or specific VCAM-1 silencing in macrophages released HSCs from spleen and reduced leukocytosis/inflammation in myocardial infarction and atherosclerosis models.\",\n      \"method\": \"Nanoparticle-mediated in vivo RNAi, CD169-iDTR macrophage depletion, flow cytometry, murine MI and atherosclerosis models\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic macrophage depletion plus RNAi-mediated VCAM-1 silencing, functionally validated with HSC retention readout, multiple approaches\",\n      \"pmids\": [\"25800955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"oxLDL-induced VCAM-1 expression and monocyte adhesion in endothelial cells requires FAK-dependent activation of p90 RSK, which in turn activates IKKβ and NF-κB. Inhibiting RSK blocks all downstream NF-κB and VCAM-1 induction. Endothelial-specific kinase-dead FAK transgenic mice show reduced RSK activity, decreased VCAM-1 expression, and reduced macrophage accumulation in early atherosclerosis.\",\n      \"method\": \"RSK pharmacological inhibition, FAK kinase-dead transgenic mice, NF-κB/IKKβ activity assay, VCAM-1 protein/mRNA, monocyte adhesion assay, in vivo atherosclerosis model\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro pathway dissection plus in vivo transgenic validation, multiple orthogonal methods\",\n      \"pmids\": [\"26906414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"VCAM-1 expressed on radial glial cells (RGCs) during embryonic development is required for the embryonic origin of adult neural stem cells (NSCs). Loss of VCAM1 in embryonic RGCs stimulates premature neuronal differentiation, prevents quiescence of slowly-dividing RGCs, and diminishes postnatal/adult NSC numbers and V-SVZ regeneration. Mechanistically, VCAM1 signals through its intracellular domain to regulate β-catenin signaling in a context-dependent manner.\",\n      \"method\": \"Conditional Vcam1 knockout mice, lineage tracing, BrdU/EdU pulse-chase, adult NSC quantification, V-SVZ regeneration assay, β-catenin reporter assay\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic KO with lineage tracing and signaling readout, multiple in vivo phenotypic assays\",\n      \"pmids\": [\"28728023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"VCAM-1 synergizes with Notch ligand DLL4 to enhance Notch signaling and progenitor T-cell differentiation from HSPCs in vitro. VCAM-1 additionally promotes an inflammatory transcriptional program in nascent HSPCs. Combined DLL4+VCAM-1 presentation on an engineered surface enhanced downstream progenitor T-cell output ~80-fold compared to DLL4 alone.\",\n      \"method\": \"Engineered stromal cell-free niche with defined protein presentation, flow cytometry for T-cell differentiation markers, Notch signaling reporter, transcriptional profiling\",\n      \"journal\": \"Nature methods\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined reconstituted system with signaling and differentiation readouts, single lab\",\n      \"pmids\": [\"28394335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"VCAM-1+ macrophage-like 'usher cells' in the zebrafish caudal haematopoietic tissue (CHT) patrol the inner surface of the venous plexus and interact with HSPCs via ITGA4 (integrin α4)-dependent interactions to direct HSPC retention in homing hotspots.\",\n      \"method\": \"High-resolution live imaging in zebrafish, cell-labelling system, ITGA4 blocking/genetic experiments, VCAM-1 expression characterization\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live in vivo imaging with genetic functional validation in zebrafish, direct observation of VCAM-1/ITGA4-dependent interaction\",\n      \"pmids\": [\"30455424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Brain endothelial VCAM1 mediates the detrimental effects of aged plasma on young brains. Aged mouse hippocampal BECs upregulate VCAM1; plasma from aged humans/mice increases VCAM1 in cultured BECs and young mouse hippocampi. Systemic anti-VCAM1 antibody or genetic Vcam1 ablation in BECs reverses microglial reactivity and cognitive deficits in aged mice and counteracts effects of aged plasma in young mice.\",\n      \"method\": \"Parabiosis/plasma transfer model, conditional BEC-specific Vcam1 knockout mice, anti-VCAM1 antibody treatment, cognitive testing, microglial activation assays\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic BEC-specific KO plus antibody neutralization, multiple in vivo functional readouts (cognition, microglial activation)\",\n      \"pmids\": [\"31086348\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Phc2, an epigenetic regulator, controls HSPC mobilization from bone marrow by transcriptionally repressing Vcam1 in bone marrow stromal cells via H3K27me3 and H2AK119ub histone modifications. Phc2 genetic ablation causes de-repression of Vcam1, retention of HSPCs, and systemic immunodeficiency; pharmacological inhibition of VCAM-1 in Phc2-deficient mice reverses these symptoms.\",\n      \"method\": \"Phc2 knockout mice, HSPC mobilization assay, chromatin immunoprecipitation (H3K27me3, H2AK119ub), VCAM-1 pharmacological inhibition rescue experiment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with chromatin-level mechanistic evidence and pharmacological rescue, multiple orthogonal methods\",\n      \"pmids\": [\"31375680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM65, an E3 ubiquitin ligase, directly interacts with VCAM-1 protein and promotes its polyubiquitination and proteasomal degradation, limiting the duration and magnitude of VCAM-1-mediated inflammation. TRIM65 and VCAM-1 expression are inversely correlated during TNFα-induced endothelial activation; wild-type but not E3-ligase-dead TRIM65 promotes VCAM-1 ubiquitination; TRIM65 knockdown attenuates VCAM-1 degradation. TRIM65-deficient mice show enhanced LPS-induced pulmonary inflammation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, E3-ligase-dead mutant, siRNA knockdown, TRIM65 KO mice, LPS-induced pulmonary inflammation model\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct interaction demonstrated by Co-IP, ubiquitination confirmed with loss-of-function mutant, in vivo KO phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"31310649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HDAC1/2 promote VCAM-1 expression by suppressing STAT3 acetylation-dependent DNMT1 recruitment to the GATA6 promoter, thereby preventing hypermethylation of GATA6 CpG regions. HDAC1/2 inhibition (Romidepsin) enhanced STAT3 acetylation, increased DNMT1-STAT3 interaction, hypermethylated the GATA6 promoter, reduced GATA6 and VCAM-1 expression, and decreased monocyte adhesion. Blocking STAT3 acetylation (Lys685Arg mutation) disrupted DNMT1-STAT3 interaction and reversed these effects.\",\n      \"method\": \"Romidepsin treatment, siRNA knockdown of HDAC1/2, methylation-specific PCR, ChIP (STAT3 binding to GATA6 promoter), STAT3 Lys685Arg point mutation, Apoe-/- mouse atherosclerosis model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — epigenetic mechanism elucidated by ChIP + methylation PCR + point mutation + in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"33859766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Macrophage VLA4 (CD49d)-endothelial VCAM1 interaction promotes vascular permeability in ovarian cancer ascites. Mechanistically, VCAM1 engagement activates RAC1 and ROS, leading to phosphorylation of PYK2 and VE-cadherin, thereby increasing endothelial paracellular permeability. Downregulation of VLA4 on M2 macrophages reduces RAC1/ROS/p-PYK2/p-VE-cad signaling and enhances barrier function. Targeting VLA4/VCAM1 augmented vascular integrity and abrogated ascites formation in vivo.\",\n      \"method\": \"VLA4/VCAM1 overexpression and knockdown, RAC1 and ROS assays, p-PYK2/p-VE-cadherin Western blot, in vivo permeability assay, anti-VLA4 antibody treatment, bevacizumab combination\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic cascade defined by gain/loss of function with in vivo validation, multiple signaling readouts\",\n      \"pmids\": [\"33295887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Membrane-bound SCF (mSCF) and VCAM-1 synergistically regulate HSC morphology and adhesion via PI3K signaling and cytoskeletal reorganization. HSCs cluster mSCF at the HSC-substrate interface and form a polarized morphology with a large protrusion when both mSCF and VCAM-1 are present on a supported lipid bilayer. This synergy dramatically enhances HSC adhesion and promotes nuclear retention of FOXO3a, a key HSC maintenance factor, reducing its loss induced by soluble SCF.\",\n      \"method\": \"Supported lipid bilayer (SLB) system, live cell imaging, PI3K pharmacological inhibition, cytoskeletal inhibitors, FOXO3a nuclear localization assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted membrane system with defined components, pharmacological dissection of signaling, multiple functional readouts\",\n      \"pmids\": [\"34402812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VCAM1 on hematopoietic stem cells (HSCs) and leukaemic stem cells (LSCs) functions as a 'don't-eat-me' signal in the context of MHC-I presentation, protecting them from phagocyte-mediated clearance. Mechanistically, VCAM1 'don't-eat-me' activity requires β2-microglobulin-dependent MHC-I presentation on HSCs and paired Ig-like receptor-B (PIR-B) on phagocytes. Vcam1 deletion in the setting of haplotype mismatch leads to HSC clearance by mononuclear phagocytes and impaired haematopoietic recovery. In AML, VCAM1 inhibition or deletion reduces leukaemia burden and extends survival.\",\n      \"method\": \"Vcam1 conditional knockout, haplotype-mismatched transplantation, MHC-I (β2m) genetic manipulation, PIR-B-expressing phagocyte assays, AML mouse model (VCAM1 inhibition)\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic dissection of immune checkpoint mechanism with multiple in vivo models, receptor-ligand pathway defined\",\n      \"pmids\": [\"35210567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VCAM-1 and DLL4 synergize to activate Notch signaling in nascent HSPCs and enhance T-cell-competent progenitor output ~80-fold from human PSCs; VCAM1 additionally promotes an inflammatory transcriptional program during the endothelial-to-haematopoietic transition.\",\n      \"method\": \"Defined serum- and feeder-free PSC differentiation system with DLL4 and VCAM1 proteins, Notch signaling reporter, transcriptional profiling, in vivo thymus colonization assay\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined reconstituted differentiation system with signaling and in vivo readouts, single lab\",\n      \"pmids\": [\"36001668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-33-induced VCAM1 in microglia directs microglial chemotaxis toward amyloid-beta (Aβ) plaques by sensing plaque-associated ApoE. Disrupting the VCAM1-ApoE interaction abolishes microglial Aβ chemotaxis and decreases Aβ clearance. Higher CSF soluble VCAM1 in AD patients correlates with impaired microglial Aβ chemotaxis.\",\n      \"method\": \"IL-33 stimulation, VCAM1 gain/loss of function in microglia, functional screening for chemotaxis, VCAM1-ApoE interaction blocking, in vivo Aβ clearance assay, human CSF correlation\",\n      \"journal\": \"Nature aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional screening identified VCAM1, interaction blocking validated mechanism, in vivo clearance readout, human translational data\",\n      \"pmids\": [\"37735240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"VCAM-1+ endothelial cell-derived extracellular vesicles (EVs) mediate rapid neutrophil mobilization from the spleen to peripheral blood after myocardial infarction. CRISPR/Cas9-mediated deletion of VCAM-1 from endothelial cells removed the ability of EC-EVs to mobilize splenic neutrophils. VCAM-1+ EVs accumulate in the spleen and induce local inflammatory gene/chemokine expression.\",\n      \"method\": \"CRISPR/Cas9 VCAM-1 KO in parent endothelial cells, EV isolation/characterization, in vivo EV administration, splenic neutrophil mobilization assay, gene expression profiling\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR-mediated deletion with functional in vivo readout, direct demonstration of VCAM-1-dependent EV function\",\n      \"pmids\": [\"35134856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In the AKI-to-CKD transition, proinflammatory cytokines (TNF-α and IL-1β) induce VCAM-1 expression in proximal tubule cells via NF-κB signaling (requiring MyD88/TRIF adaptors). TNF-α stimulation or VCAM-1 overexpression increases CD45+ splenocyte adhesion to tubular monolayers; NF-κB inhibition or Vcam1 genetic deletion suppresses TNF-α-induced splenocyte adhesion, demonstrating a proximal tubule-immune cell cross-talk role for VCAM-1.\",\n      \"method\": \"TNF-α/IL-1β stimulation of primary renal cells, NF-κB pharmacological inhibition, MyD88/TRIF genetic deletion, VCAM-1 overexpression, splenocyte adhesion assay, single-cell transcriptomics of patient biopsies\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway dissection with pharmacological and genetic tools, functional adhesion readout, single lab\",\n      \"pmids\": [\"39116349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"VCAM-1 and VAP-1 on tumor-activated pulmonary endothelium recruit myeloid cells that promote tumor cell survival and metastasis. VCAM-1 induction depends on tumor cell-clot formation (blocked by tissue factor pathway inhibitor or hirudin). Anti-VCAM-1 blocking antibody reduces myeloid cell recruitment and tumor cell survival without affecting tumor cell adhesion.\",\n      \"method\": \"VCAM-1 antibody blocking, tissue factor pathway inhibitor, hirudin treatment, in vivo myeloid cell recruitment assay, tumor survival/metastasis assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody blocking with mechanistic upstream dissection (coagulation dependency) and in vivo metastasis readout, single lab\",\n      \"pmids\": [\"23407548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CAF-derived VCAM1 (upregulated by H. pylori infection via JAK/STAT1 signaling) molecularly interacts with integrin αvβ1/5 on gastric cancer cells to facilitate tumor invasion. The kinetic binding interaction between VCAM1 and integrin αvβ1/5 was directly measured by biolayer interferometry.\",\n      \"method\": \"RNA-seq, biolayer interferometry (direct binding kinetics), spheroid invasion assay, zebrafish xenograft model, JAK/STAT1 inhibition\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding kinetics by BLI plus functional invasion assay and in vivo model, single lab\",\n      \"pmids\": [\"32034307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Endothelial Notch1 intracellular domain (N1ICD) upregulates VCAM1 expression and amplifies IL-1β-mediated VCAM1 induction through a Notch1-Jagged1 autocrine circuit. Forced N1ICD expression upregulated VCAM1 per se; γ-secretase inhibition or Notch1/Jagged1 silencing reduced IL-1β-mediated VCAM1 induction. IL-1β decreases Notch1 mRNA but maintains active N1ICD protein levels.\",\n      \"method\": \"γ-secretase inhibitor, Notch1/Jagged1 siRNA silencing, N1ICD forced expression, Western blot (Notch1ICD, Jagged1), VCAM1 promoter reporter, liver inflammation model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss of function for Notch1 and Jagged1 with VCAM1 readout, single lab\",\n      \"pmids\": [\"26646450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FSH promotes endothelial VCAM-1 expression via FSHR located in membrane caveolae interacting with caveolin-1 and GαS, leading to cAMP/PKA elevation and PI3K/Akt/mTOR/NF-κB activation. Disruption of caveolae or caveolin-1 silencing blocks FSH-induced signaling and VCAM-1 expression. FSH increases monocyte adhesion to HUVECs, reversed by VCAM-1 neutralizing antibody.\",\n      \"method\": \"Luciferase reporter assay, transfection, flow chamber adhesion assay, Western blot, caveolae disruption, caveolin-1 siRNA, PI3K/Akt/mTOR inhibitors, NF-κB luciferase, VCAM-1 neutralizing antibody, ApoE KO atherosclerosis mouse model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-step signaling pathway defined with pharmacological and genetic tools, in vivo validation, single lab\",\n      \"pmids\": [\"29187895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In MLL-fusion AML, IMPDH inhibition induces overactivation of TLR-TRAF6-NF-κB signaling and upregulation of VCAM1, which contributes to the antileukemia effect. Combined treatment with IMPDH inhibitors and TLR1/2 agonist effectively inhibited MLL-fusion AML development in vivo.\",\n      \"method\": \"In vitro IMPDH inhibitor treatment, NF-κB signaling assay, VCAM1 expression analysis, in vivo AML mouse model, TLR1/2 agonist combination\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — signaling pathway identified with in vivo functional validation, single lab\",\n      \"pmids\": [\"36453131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VCAM1 expression in ovarian theca and stromal cells is induced by androgen receptor (AR) signaling; AR antagonist flutamide markedly reduces VCAM1 mRNA and protein in PCOS-derived theca cells. VCAM1 expression is specifically elevated in NR2F2/COUPTF-II lineage theca cells, not granulosa cells, of DHT-treated mice. LH (equine chorionic gonadotropin) transiently induces VCAM1, while hCG (superovulatory dose) potently suppresses it.\",\n      \"method\": \"Genome-wide microarray, DHT-treatment mouse model, AR antagonist (flutamide) treatment, immunohistochemistry, RT-PCR, PCOS-derived human theca cell culture\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological AR antagonism and in vivo DHT model, single lab\",\n      \"pmids\": [\"30951142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"VCAM1 on the uterine endometrial epithelium and trophoblast ITGA4 (integrin α4) mediate bovine conceptus adhesion to the uterine endometrium during implantation. VCAM1 and ITGA4 expression are mutually upregulated by co-culture of endometrial epithelial cells (EECs) with bovine trophoblast CT1 cells and by uterine flushings. ITGA4 protein is localized specifically to trophoblasts in day-22 pregnant uteri.\",\n      \"method\": \"Co-culture of EEC and CT1 trophoblast cells, immunohistochemistry (VCAM1, ITGA4 localization), RT-PCR, Western blot, uterine flushing treatment\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-culture system with localization and expression readouts, single lab\",\n      \"pmids\": [\"24803492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In AML driven by IRF7 loss, VCAM1 is upregulated (correlated with elevated LSC levels), and VCAM1-VLA-4 axis mediates intracerebral invasion of AML cells. Blocking the VCAM1-VLA-4 axis delayed disease progression and attenuated intracerebral invasion in IRF7-/- AML mouse models.\",\n      \"method\": \"IRF7 KO and overexpression in MLL-AF9 AML model, xenograft mouse model, VCAM1 expression analysis, anti-VCAM1/anti-VLA-4 antibody blocking, intracranial invasion assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic AML model with antibody blocking and in vivo invasion readout, single lab\",\n      \"pmids\": [\"35256780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Notch1-c-myc-VCAM1 signaling axis drives macrophage-dependent HCC transendothelial migration and pulmonary metastasis. Elevated Notch1 increases c-myc, which transcriptionally upregulates VCAM1. Silencing c-myc prohibits tumorigenicity; VCAM1 depletion reduces spontaneous lung metastasis without affecting primary tumor growth. Macrophage depletion or blockade of macrophage α4β1-integrin (VCAM1 receptor) reduces lung nodule formation.\",\n      \"method\": \"N1ICD overexpression in LPC, c-myc and VCAM1 siRNA/shRNA, orthotopic rat liver tumor model, macrophage depletion, α4β1 integrin blocking antibody, experimental metastasis model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptional pathway defined with gain/loss of function, macrophage-dependent mechanism validated in vivo, single lab\",\n      \"pmids\": [\"35256782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NF-κB regulates CD106 (VCAM1) expression in bone marrow mesenchymal stem cells, and CD106 supports hematopoiesis. CD106+ MSCs show increased in vitro capillary tube-like formation, vasculogenesis, and in vivo engraftment of CD34+ cells compared to CD106- MSCs. TNF-α and LPS stimulation of MSCs confirms NF-κB-mediated induction of VCAM1.\",\n      \"method\": \"Flow cytometry, Illumina HiSeq sequencing, qRT-PCR, Western blot, NF-κB inhibition (blockade assay, immunofluorescence), CD34+ cell engraftment in NOD/SCID mice, colony-forming assays\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — NF-κB pathway confirmed by blockade with functional engraftment readout, single lab\",\n      \"pmids\": [\"28764810\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"VCAM1 is a transmembrane immunoglobulin superfamily glycoprotein expressed on activated endothelial cells, stromal cells, and select progenitor populations; it binds α4β1 (VLA-4/CD49d) and αMβ2 integrins through its Ig domains 1 and 4, mediating leukocyte and stem cell adhesion/migration, while its intracellular domain signals via β-catenin, NADPH oxidase/ROS, and p38 MAPK pathways; its expression is transcriptionally controlled by NF-κB, IRF-1, GATA4/GATA6, Notch1-Jagged1, and Wnt/β-catenin, and post-translationally regulated by TRIM65 E3 ligase-mediated ubiquitination/degradation and metalloprotease-dependent ectodomain shedding to soluble sVCAM-1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"VCAM1 is a transmembrane immunoglobulin-superfamily adhesion glycoprotein expressed on cytokine-activated endothelium, bone marrow and splenic stroma, and select progenitor and macrophage populations, where it governs leukocyte and stem-cell adhesion, migration, and retention across immune, vascular, hematopoietic, and neural contexts [#2, #11, #19]. Its extracellular Ig modules engage integrin counter-receptors with domain specificity: domains 1 and 4 each independently support α4β1 (VLA-4)-mediated leukocyte transendothelial migration, while the module 4–7 region additionally binds αMβ2 in a PI3K-dependent manner [#4, #14]. Beyond passive tethering, VCAM-1 ligation is a bidirectional signaling event — cross-linking activates phosphoinositide/Ca2+ flux and drives NADPH-oxidase-derived ROS and RAC1 signaling that phosphorylates VE-cadherin to open endothelial junctions for transmigration and to increase vascular permeability [#5, #28]. The gene is transcriptionally induced by NF-κB downstream of TNF, IL-1, LPS, and thrombin, amplified by IRF-1, Notch1–Jagged1, GATA factors, and HDAC1/2–GATA6 circuits, and repressed by Wnt/β-catenin and Polycomb (Phc2)-mediated H3K27me3/H2AK119ub [#2, #7, #8, #16, #27, #37, #15, #25]. Surface levels are further set post-transcriptionally by p38 MAPK and post-translationally by TRIM65 E3-ligase-mediated polyubiquitination/degradation and by metalloprotease- and neutrophil-protease-dependent ectodomain shedding that releases soluble VCAM-1 [#6, #26, #3, #10]. Functionally, VCAM-1 is a dominant initiator of atherosclerotic lesion formation, retains hematopoietic and neural stem cells in their niches, acts via its intracellular domain on β-catenin to specify adult neural stem cells, mediates aged-plasma-driven cognitive decline through brain endothelium, directs microglial chemotaxis to amyloid-β by sensing ApoE, and serves as a β2-microglobulin/MHC-I-dependent 'don't-eat-me' signal protecting hematopoietic and leukemic stem cells from PIR-B-bearing phagocytes [#11, #19, #21, #24, #32, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing the genomic architecture and promoter of VCAM1 defined how the gene is regulated and how isoform diversity arises, anchoring all later regulatory studies.\",\n      \"evidence\": \"Genomic cloning, exon mapping, and promoter sequence analysis of the human (and later murine) gene\",\n      \"pmids\": [\"1715583\", \"7507076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequences of exon-5 alternative splicing and the PI-anchored isoform not resolved\", \"Promoter elements identified by sequence but not yet functionally dissected\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Demonstrating cytokine-inducible VCAM-1 mediating VLA-4-dependent leukocyte adhesion to endothelium established its core role as an inflammatory adhesion receptor.\",\n      \"evidence\": \"Flow cytometry and monoclonal antibody blocking adhesion assays on cytokine-activated murine microvascular endothelium\",\n      \"pmids\": [\"7680963\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not map which Ig domains mediate binding\", \"Single-lab antibody-based evidence\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Mapping adhesion to Ig domains 1 and 4 and showing regulated metalloprotease shedding defined both the ligand-binding architecture and a mechanism for generating soluble VCAM-1.\",\n      \"evidence\": \"Domain-specific antibody blocking with CHO transfectants in transmigration assays; immunoprecipitation with metalloprotease inhibitors for shedding\",\n      \"pmids\": [\"7545712\", \"7529789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the physiological sheddase not defined\", \"Function of soluble VCAM-1 not addressed\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showing that VCAM-1 cross-linking triggers phosphoinositide/Ca2+ signaling and that p38 MAPK controls surface expression post-transcriptionally established VCAM-1 as a bidirectional signaling molecule, not merely a static ligand.\",\n      \"evidence\": \"Fura-2/IP3 assays with antibody cross-linking; p38 inhibitor (SB203580) with mRNA vs surface-protein readouts in TNFα-stimulated endothelium\",\n      \"pmids\": [\"9209507\", \"9020057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intracellular effectors linking cross-linking to Ca2+ not identified\", \"p38 target controlling surface trafficking unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defining IRF-1 as required for IFN amplification of TNF-induced transcription and thrombin as an NF-κB-independent inducer expanded the upstream regulatory network beyond canonical cytokines.\",\n      \"evidence\": \"CAT reporter, EMSA, and IRF-1/IRF-2 transfection; thrombin receptor peptide and hirudin with adhesion readouts on HUVECs\",\n      \"pmids\": [\"9625761\", \"9694714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Combinatorial logic between IRF-1 and NF-κB at the promoter not fully resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Genetic hypomorph studies showing VCAM-1 (not ICAM-1) dominates atherosclerosis initiation, plus protease cleavage during HPC mobilization, established VCAM-1 as a causal driver of disease and a regulated niche-retention molecule.\",\n      \"evidence\": \"Hypomorphic Vcam1(D4D) allele in LDLR-null mice with en face lesion quantification; in vivo G-CSF mobilization with neutrophil elastase/cathepsin G cleavage\",\n      \"pmids\": [\"11375415\", \"11520773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific contributions to lesion initiation not dissected\", \"Whether shedding is cause or consequence of mobilization unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Reconstituting eosinophil adhesion with domain-specific constructs confirmed dual integrin usage — α4β1 across the molecule and αMβ2 on module 4 in a PI3K-dependent, flow-modulated manner — refining the ligand map.\",\n      \"evidence\": \"Recombinant domain constructs, antibody blocking, PI3K inhibitor, and αMβ2-null cell lines under static and flow adhesion\",\n      \"pmids\": [\"16943205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of αMβ2 module-4 binding not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying nuclear FAK–GATA4/CHIP control and reciprocal IRF-1/miR-126 regulation revealed that VCAM-1 transcription is gated at the transcription-factor stability and microRNA levels under inflammatory and lipoprotein stimuli.\",\n      \"evidence\": \"FAK genetic/pharmacological perturbation with FERM–GATA4 binding and ubiquitination assays; IRF-1 and miR-126 gain/loss of function with TGRL stimulation\",\n      \"pmids\": [\"22734001\", \"22874466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of FAK/GATA4 axis with NF-κB and IRF-1 inputs not unified\", \"miR-126 direct target sites on VCAM1 not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showing tumor SPARC and pulmonary endothelial VCAM-1/VAP-1 promote permeability, myeloid recruitment, and metastasis, and that splenic VCAM-1+ macrophages retain HSCs, broadened VCAM-1 function into cancer dissemination and stem-cell niche control.\",\n      \"evidence\": \"SPARC knockout/overexpression with anti-VCAM1 blocking and in vivo permeability/extravasation; coagulation-dependent VCAM-1 induction; nanoparticle-RNAi and CD169-iDTR macrophage depletion with HSC retention readouts\",\n      \"pmids\": [\"25925867\", \"23407548\", \"25800955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How VCAM-1 signaling distinguishes adhesion from permeability outputs not resolved\", \"Upstream signal coupling SPARC to endothelial VCAM-1 p38 not fully traced\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Conditional knockout in radial glia demonstrated a developmental, cell-intrinsic role for VCAM-1 acting through its intracellular domain on β-catenin to establish adult neural stem cells, plus a synthetic role synergizing with DLL4/Notch in HSPC and T-cell progenitor specification.\",\n      \"evidence\": \"Conditional Vcam1 knockout with lineage tracing and β-catenin reporters; engineered DLL4+VCAM-1 surfaces with Notch reporters and T-progenitor output\",\n      \"pmids\": [\"28728023\", \"28394335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of intracellular-domain effectors coupling to β-catenin not defined\", \"Whether Notch synergy requires VCAM-1 signaling or only co-presentation unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing brain endothelial VCAM-1 as the mediator of aged-plasma effects on cognition, and Polycomb (Phc2) repression of stromal Vcam1 controlling HSPC mobilization, linked VCAM-1 to aging neuroinflammation and epigenetically gated hematopoiesis.\",\n      \"evidence\": \"BEC-specific Vcam1 KO and anti-VCAM1 antibody with cognitive/microglial readouts; Phc2 KO with H3K27me3/H2AK119ub ChIP and VCAM-1 inhibition rescue\",\n      \"pmids\": [\"31086348\", \"31375680\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Plasma factor inducing endothelial VCAM-1 in aging not identified\", \"Whether VCAM-1 signals into BECs or recruits leukocytes to cause cognitive deficit not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying TRIM65 as a direct E3 ligase driving VCAM-1 polyubiquitination/degradation defined a post-translational brake limiting inflammation duration.\",\n      \"evidence\": \"Co-IP, ubiquitination assays with E3-dead mutant, siRNA, and TRIM65 KO mice in LPS pulmonary inflammation\",\n      \"pmids\": [\"31310649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lysine residues targeted on VCAM-1 not mapped\", \"Signals that activate TRIM65 toward VCAM-1 unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mechanistic dissection of VCAM-1 outside-in signaling (RAC1/ROS/PYK2/VE-cadherin), epigenetic HDAC1/2–STAT3–DNMT1–GATA6 control, and SCF/PI3K synergy maintaining FOXO3a clarified how VCAM-1 simultaneously regulates permeability, its own transcription, and stem-cell maintenance.\",\n      \"evidence\": \"VLA4/VCAM1 gain/loss with RAC1/ROS and p-PYK2/p-VE-cad readouts in ovarian ascites; Romidepsin/HDAC siRNA with methylation PCR and STAT3 K685R; supported lipid bilayer with PI3K inhibition and FOXO3a localization\",\n      \"pmids\": [\"33295887\", \"33859766\", \"34402812\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct intracellular VCAM-1 binding partners transmitting RAC1 signal not identified\", \"How membrane-bound SCF and VCAM-1 co-cluster mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defining VCAM-1 as a β2m/MHC-I-dependent 'don't-eat-me' signal engaging phagocyte PIR-B, and as a Notch/c-myc-driven mediator of leukemic and HCC dissemination, repositioned VCAM-1 as an immune checkpoint and metastasis effector with therapeutic implications.\",\n      \"evidence\": \"Vcam1 conditional KO with haplotype-mismatched transplant, β2m manipulation, and PIR-B phagocyte assays; AML/HCC models with Notch1-c-myc-VCAM1 axis and α4β1 blockade\",\n      \"pmids\": [\"35210567\", \"35256780\", \"35256782\", \"36453131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of VCAM-1/PIR-B engagement vs integrin binding not resolved\", \"Whether VCAM-1 checkpoint and adhesion functions are separable not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing IL-33-induced microglial VCAM-1 senses plaque ApoE to direct chemotaxis and Aβ clearance, and that VCAM-1+ endothelial EVs mobilize splenic neutrophils after MI, revealed cell-autonomous and vesicle-mediated VCAM-1 functions beyond endothelial adhesion.\",\n      \"evidence\": \"VCAM1 gain/loss in microglia with VCAM1-ApoE interaction blocking and Aβ clearance, plus human CSF correlation; CRISPR VCAM-1 KO in EC-EVs with in vivo neutrophil mobilization\",\n      \"pmids\": [\"37735240\", \"35134856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether VCAM1-ApoE binding is direct and its structural interface unknown\", \"How VCAM-1 on EVs signals to splenic targets not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating NF-κB/MyD88/TRIF-dependent VCAM-1 induction in proximal tubule cells driving immune-cell adhesion extended the inflammatory-adhesion paradigm to the AKI-to-CKD transition.\",\n      \"evidence\": \"TNF-α/IL-1β stimulation of primary renal cells with NF-κB inhibition, MyD88/TRIF deletion, VCAM-1 overexpression, and splenocyte adhesion assays plus patient single-cell data\",\n      \"pmids\": [\"39116349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional data\", \"In vivo causal contribution of tubular VCAM-1 to fibrosis not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intracellular domain effectors that couple VCAM-1 ligation to β-catenin, RAC1/ROS, and Ca2+ signaling remain unidentified, and the structural distinction between its integrin-binding, ApoE-sensing, and PIR-B checkpoint functions is unresolved.\",\n      \"evidence\": \"No direct cytoplasmic-tail interactor or structural study in the timeline\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No defined cytoplasmic-domain binding partner\", \"No structural model of the multiple ligand interfaces\", \"Whether adhesion, signaling, and checkpoint functions are separable not tested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 4, 14, 23, 41]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 28, 21]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3, 4, 14]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 32]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 4, 14, 34]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [11, 18, 24, 30, 42]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 20, 28]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [21, 23, 41]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ITGA4\", \"ITGB1\", \"ITGAM\", \"ITGB2\", \"TRIM65\", \"ITGAV\", \"APOE\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}