{"gene":"BDKRB1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1996,"finding":"The human BDKRB1 gene contains three exons (first and second noncoding, third containing the entire coding region) separated by two introns, is encoded by a single-copy gene, and has multiple transcription initiation sites identified by primer extension experiments downstream and upstream of a consensus TATA box.","method":"Genomic library cloning, sequencing, primer extension, genomic Southern blot","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cloning, sequencing, and primer extension in a single focused study with multiple complementary methods","pmids":["8660997"],"is_preprint":false},{"year":1996,"finding":"A 300-bp fragment in the BDKRB1 promoter region is sufficient to direct reporter gene synthesis, and an enhancer-like element is present between -1842 and -812, as determined by deletion analysis with a CAT reporter. The gene is located on chromosome 14q32.1-q32.2, in close proximity to the B2 receptor gene.","method":"CAT reporter deletion analysis, chromosomal localization, genomic Southern blot, Northern blot, RT-PCR","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter deletion analysis with reporter assay and chromosomal localization, single lab with multiple orthogonal methods","pmids":["8808279"],"is_preprint":false},{"year":2005,"finding":"In vivo DNase I footprinting in smooth muscle cells (SMCs) that express functional BDKRB1 revealed distinct protein-DNA interactions at the BDKRB1 core promoter compared to lymphocytes (which lack BDKRB1 expression, showing nucleosome-like patterns). Gel-shift assays identified YY1 and TBP/TFIIB as transcription factors binding the BDKRB1 promoter in SMCs, with YY1 possibly involved in NF-κB-mediated regulation of BDKRB1 expression.","method":"In vivo DNase I footprinting, dimethyl sulfate and UV-C footprinting, gel-shift (EMSA) assays","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo footprinting combined with EMSA in a single lab, two orthogonal methods with cell-type comparison","pmids":["15705059"],"is_preprint":false},{"year":2025,"finding":"BDKRB1 activation in neutrophils during sepsis induces CXCR2 desensitization, impairing neutrophil migration. Genetic deletion of Bdkrb1 in mice subjected to cecal ligation and puncture (CLP) restored partial CXCR2 expression, reduced P110γ upregulation, increased peritoneal neutrophil influx, decreased bacterial load, and reduced lethality. In human neutrophils, BDKRB1 antagonism restored migration in response to CXCL8.","method":"Bdkrb1 knockout mice (CLP model), flow cytometry for CXCR2/P110γ, pharmacological BDKRB1 inhibition, human neutrophil migration assays","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined cellular phenotype corroborated by pharmacological inhibition and human neutrophil experiments, multiple orthogonal methods","pmids":["41355798"],"is_preprint":false},{"year":2025,"finding":"Mechanical stress (10% amplitude) upregulates BDKRB1 expression and activates a BDKRB1/Ca²⁺/CaMKII/MEK1/ERK signaling axis in alveolar epithelial cells (RLE-6TN), promoting cell proliferation and calcium influx. BDKRB1 knockdown attenuated both the growth and calcium influx increases induced by 10% mechanical stress and blocked activation of the downstream Ca²⁺/CaMKII/MEK1/ERK pathway.","method":"siRNA knockdown, RT-qPCR, western blotting, flow cytometry (calcium), CCK-8, EDU staining","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (knockdown) with defined pathway readout by western blot and functional assays, single lab","pmids":["40296124"],"is_preprint":false},{"year":2026,"finding":"Transcription factor TFAP2A directly binds the BDKRB1 promoter and transcriptionally activates BDKRB1 expression, driving EMT progression in pulmonary fibrosis. TFAP2A knockdown reduced BDKRB1 RNA levels and protected against BLM-induced fibrosis, while BDKRB1 overexpression abrogated these protective effects.","method":"Promoter binding assay (TFAP2A ChIP/binding to BDKRB1 promoter), lentiviral knockdown, adenoviral shRNA, in vivo BLM mouse model, in vitro BEAS-2B cell assays, RT-PCR, western blot","journal":"Toxicology and applied pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding demonstrated with rescue (BDKRB1 overexpression reversal), single lab, multiple methods including in vivo and in vitro","pmids":["41587695"],"is_preprint":false},{"year":2026,"finding":"METTL1-mediated N7-methylguanosine (m7G) modification stabilizes Bdkrb1 mRNA in epidermal keratinocytes, increasing BDKRB1 protein expression. Elevated BDKRB1 activates the p38 MAPK pathway, promoting secretion of CXCL chemokines and neutrophil chemotaxis in psoriasis. Keratinocyte-specific Mettl1 deletion attenuated psoriasiform inflammation and neutrophil infiltration, and both BDKRB1 overexpression and pharmacological BDKRB1 activation rescued this attenuated phenotype.","method":"Inducible keratinocyte-specific Mettl1 knockout mice (Mettl1fl/fl Krt14-CreERT2), m7G modification analysis, BDKRB1 overexpression rescue, pharmacological BDKRB1 activation, western blot, chemokine secretion assays, neutrophil chemotaxis assays","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with genetic rescue by BDKRB1 overexpression and pharmacological rescue, multiple orthogonal methods establishing the METTL1→m7G→Bdkrb1 mRNA stability→p38→CXCL→neutrophil axis","pmids":["42261843"],"is_preprint":false}],"current_model":"BDKRB1 (bradykinin B1 receptor) is a single-copy, inflammation-inducible GPCR whose transcription is driven by a 300-bp core promoter element (with a distal enhancer between -1842 and -812), regulated by YY1 and TBP/TFIIB, and directly transactivated by TFAP2A; at the post-transcriptional level, METTL1-mediated m7G modification stabilizes BDKRB1 mRNA; upon activation, BDKRB1 signals through Ca²⁺/CaMKII/MEK1/ERK to promote cell proliferation, activates p38 MAPK to drive CXCL chemokine secretion and neutrophil chemotaxis, and in neutrophils induces CXCR2 desensitization (via P110γ upregulation) to impair bacterial clearance during sepsis."},"narrative":{"mechanistic_narrative":"BDKRB1 (bradykinin B1 receptor) is an inflammation-inducible G-protein-coupled receptor that couples extracellular stimuli to pro-inflammatory and proliferative signaling, encoded by a single-copy gene whose expression is tightly transcriptionally controlled [PMID:8660997, PMID:15705059]. Its core promoter resides within a 300-bp fragment sufficient to drive reporter expression, with an additional enhancer-like element between -1842 and -812; the gene maps to chromosome 14q32.1-q32.2 near the B2 receptor gene [PMID:8808279]. In cells that express the receptor, the core promoter is occupied by YY1 and the basal factors TBP/TFIIB, a pattern absent in non-expressing lymphocytes, and YY1 is implicated in NF-κB-linked regulation [PMID:15705059]. BDKRB1 is further induced by the transcription factor TFAP2A, which binds the promoter directly and drives epithelial-mesenchymal transition in pulmonary fibrosis [PMID:41587695], and is stabilized post-transcriptionally by METTL1-mediated m7G modification of its mRNA in keratinocytes [PMID:42261843]. Once expressed, BDKRB1 transduces signals through distinct effector arms: a Ca²⁺/CaMKII/MEK1/ERK axis that promotes calcium influx and cell proliferation in mechanically stressed alveolar epithelial cells [PMID:40296124], and a p38 MAPK pathway that drives CXCL chemokine secretion and neutrophil chemotaxis in psoriatic inflammation [PMID:42261843]. In sepsis, BDKRB1 activation in neutrophils induces CXCR2 desensitization with upregulation of P110γ, impairing neutrophil migration and bacterial clearance, such that Bdkrb1 deletion or antagonism restores migration and reduces lethality [PMID:41355798].","teleology":[{"year":1996,"claim":"Established the genomic architecture and basal transcriptional landscape of BDKRB1, defining it as a single-copy gene whose coding region lies in a single exon under control of a TATA-box-containing promoter with multiple start sites.","evidence":"Genomic cloning, sequencing, and primer extension of the human gene","pmids":["8660997"],"confidence":"Medium","gaps":["Did not identify the trans-acting factors controlling transcription","No functional dissection of the promoter elements"]},{"year":1996,"claim":"Localized the cis-regulatory elements controlling BDKRB1, showing a 300-bp core promoter sufficient for expression plus a distal enhancer, and mapped the gene adjacent to the B2 receptor gene.","evidence":"CAT reporter deletion analysis and chromosomal localization","pmids":["8808279"],"confidence":"Medium","gaps":["Did not identify which proteins bind these elements","Enhancer mechanism and tissue-specificity not resolved"]},{"year":2005,"claim":"Connected cell-type-specific BDKRB1 expression to defined promoter occupancy, identifying YY1 and TBP/TFIIB as factors bound in expressing smooth muscle cells but not in non-expressing lymphocytes.","evidence":"In vivo DNase I/DMS/UV footprinting and EMSA in SMCs versus lymphocytes","pmids":["15705059"],"confidence":"Medium","gaps":["YY1 link to NF-κB regulation not directly demonstrated","No functional knockdown of YY1 to confirm requirement for expression"]},{"year":2025,"claim":"Defined a pathogenic role for BDKRB1 in sepsis by showing its activation desensitizes CXCR2 via P110γ to block neutrophil migration and bacterial clearance.","evidence":"Bdkrb1 knockout mice in CLP model, flow cytometry, pharmacological inhibition, and human neutrophil migration assays","pmids":["41355798"],"confidence":"High","gaps":["Mechanism linking BDKRB1 to P110γ upregulation not resolved","Direct molecular coupling between BDKRB1 and CXCR2 desensitization unknown"]},{"year":2025,"claim":"Identified mechanical stress as an inducer of BDKRB1 and traced a downstream Ca²⁺/CaMKII/MEK1/ERK axis driving epithelial proliferation.","evidence":"siRNA knockdown with western blot, calcium flow cytometry, and proliferation assays in alveolar epithelial cells","pmids":["40296124"],"confidence":"Medium","gaps":["Mechanism by which mechanical stress upregulates BDKRB1 not defined","G-protein coupling linking receptor to calcium influx not characterized"]},{"year":2026,"claim":"Established TFAP2A as a direct transcriptional activator of BDKRB1 driving EMT in pulmonary fibrosis, with BDKRB1 acting downstream of TFAP2A.","evidence":"Promoter binding assay, lentiviral/adenoviral knockdown, BLM mouse model with BDKRB1 overexpression rescue","pmids":["41587695"],"confidence":"Medium","gaps":["Signaling pathway linking BDKRB1 to EMT not detailed","Whether TFAP2A acts at the core promoter or enhancer not specified"]},{"year":2026,"claim":"Revealed post-transcriptional control of BDKRB1 by METTL1-mediated m7G mRNA modification and linked elevated BDKRB1 to p38-driven CXCL secretion and neutrophil recruitment in psoriasis.","evidence":"Keratinocyte-specific Mettl1 knockout mice with BDKRB1 overexpression and pharmacological rescue, m7G analysis, chemokine and chemotaxis assays","pmids":["42261843"],"confidence":"High","gaps":["Direct demonstration of m7G sites on Bdkrb1 mRNA not detailed","Mechanism coupling BDKRB1 to p38 activation not resolved"]},{"year":null,"claim":"How BDKRB1 selects among its divergent downstream effector arms (Ca²⁺/CaMKII/MEK1/ERK versus p38/CXCL versus CXCR2 desensitization) in a tissue- and stimulus-specific manner remains unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or G-protein-coupling data defining receptor signaling bias","Ligand-dependence of the distinct downstream pathways not dissected","No unified model of how transcriptional and post-transcriptional inputs converge on receptor output"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,4,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,4,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,6]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P46663","full_name":"B1 bradykinin receptor","aliases":[],"length_aa":353,"mass_kda":40.5,"function":"This is a receptor for bradykinin. Could be a factor in chronic pain and inflammation","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P46663/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BDKRB1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BDKRB1","total_profiled":1310},"omim":[{"mim_id":"616604","title":"CHROMOSOME 14q32 DUPLICATION SYNDROME, 700-KB","url":"https://www.omim.org/entry/616604"},{"mim_id":"600337","title":"BRADYKININ RECEPTOR B1; BDKRB1","url":"https://www.omim.org/entry/600337"},{"mim_id":"113503","title":"BRADYKININ RECEPTOR B2; BDKRB2","url":"https://www.omim.org/entry/113503"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"urinary bladder","ntpm":21.8}],"url":"https://www.proteinatlas.org/search/BDKRB1"},"hgnc":{"alias_symbol":["BKR1","B1BKR","bradyb1"],"prev_symbol":[]},"alphafold":{"accession":"P46663","domains":[{"cath_id":"1.20.1070.10","chopping":"31-235_245-321","consensus_level":"medium","plddt":91.6506,"start":31,"end":321}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P46663","model_url":"https://alphafold.ebi.ac.uk/files/AF-P46663-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P46663-F1-predicted_aligned_error_v6.png","plddt_mean":85.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BDKRB1","jax_strain_url":"https://www.jax.org/strain/search?query=BDKRB1"},"sequence":{"accession":"P46663","fasta_url":"https://rest.uniprot.org/uniprotkb/P46663.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P46663/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P46663"}},"corpus_meta":[{"pmid":"8660997","id":"PMC_8660997","title":"Structure and genomic organization of the human B1 receptor gene for kinins (BDKRB1).","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8660997","citation_count":61,"is_preprint":false},{"pmid":"8808279","id":"PMC_8808279","title":"Genomic DNA sequence, expression, and chromosomal localization of the human B1 bradykinin receptor gene BDKRB1.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8808279","citation_count":46,"is_preprint":false},{"pmid":"15705059","id":"PMC_15705059","title":"In vivo DNase I-mediated footprinting analysis along the human bradykinin B1 receptor (BDKRB1) gene promoter: evidence for cell-specific regulation.","date":"2005","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/15705059","citation_count":9,"is_preprint":false},{"pmid":"34828323","id":"PMC_34828323","title":"The Expression of RAAS Key Receptors, Agtr2 and Bdkrb1, Is Downregulated at an Early Stage in a Rat Model of Wolfram Syndrome.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/34828323","citation_count":5,"is_preprint":false},{"pmid":"31017477","id":"PMC_31017477","title":"The G Allele of the rs12050217 Polymorphism in the BDKRB1 Gene Is Associated with Protection for Diabetic Retinopathy.","date":"2019","source":"Current eye research","url":"https://pubmed.ncbi.nlm.nih.gov/31017477","citation_count":5,"is_preprint":false},{"pmid":"40296124","id":"PMC_40296124","title":"Mechanical stress facilitates calcium influx and growth of alveolar epithelial cells via activation of the BDKRB1/Ca2+/CaMKII/MEK1/ERK axis.","date":"2025","source":"Respiratory research","url":"https://pubmed.ncbi.nlm.nih.gov/40296124","citation_count":3,"is_preprint":false},{"pmid":"41355798","id":"PMC_41355798","title":"BDKRB1 activation induces CXCR2 desensitization in neutrophils during severe sepsis and exacerbates disease severity.","date":"2025","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/41355798","citation_count":1,"is_preprint":false},{"pmid":"42088621","id":"PMC_42088621","title":"BDKRB1 Links Copy Number-Defined Genomic Instability to Inflammatory and Immunosuppressive Tumor Ecosystems in Ovarian Cancer: An Integrative Multiomics Analysis.","date":"2026","source":"International journal of genomics","url":"https://pubmed.ncbi.nlm.nih.gov/42088621","citation_count":0,"is_preprint":false},{"pmid":"41587695","id":"PMC_41587695","title":"Transcription factor TFAP2A drives EMT progress by activating BDKRB1 transcription: The potential mechanism by which TFAP2A promotes idiopathic pulmonary fibrosis.","date":"2026","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41587695","citation_count":0,"is_preprint":false},{"pmid":"42261843","id":"PMC_42261843","title":"Epidermal METTL1-Mediated m7G Modification Drives Psoriatic Inflammation by Stabilizing Bdkrb1 and Orchestrating Neutrophil Recruitment.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/42261843","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7845,"output_tokens":2182,"usd":0.028133,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9147,"output_tokens":2889,"usd":0.05898,"stage2_stop_reason":"end_turn"},"total_usd":0.087113,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"The human BDKRB1 gene contains three exons (first and second noncoding, third containing the entire coding region) separated by two introns, is encoded by a single-copy gene, and has multiple transcription initiation sites identified by primer extension experiments downstream and upstream of a consensus TATA box.\",\n      \"method\": \"Genomic library cloning, sequencing, primer extension, genomic Southern blot\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cloning, sequencing, and primer extension in a single focused study with multiple complementary methods\",\n      \"pmids\": [\"8660997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"A 300-bp fragment in the BDKRB1 promoter region is sufficient to direct reporter gene synthesis, and an enhancer-like element is present between -1842 and -812, as determined by deletion analysis with a CAT reporter. The gene is located on chromosome 14q32.1-q32.2, in close proximity to the B2 receptor gene.\",\n      \"method\": \"CAT reporter deletion analysis, chromosomal localization, genomic Southern blot, Northern blot, RT-PCR\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter deletion analysis with reporter assay and chromosomal localization, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"8808279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In vivo DNase I footprinting in smooth muscle cells (SMCs) that express functional BDKRB1 revealed distinct protein-DNA interactions at the BDKRB1 core promoter compared to lymphocytes (which lack BDKRB1 expression, showing nucleosome-like patterns). Gel-shift assays identified YY1 and TBP/TFIIB as transcription factors binding the BDKRB1 promoter in SMCs, with YY1 possibly involved in NF-κB-mediated regulation of BDKRB1 expression.\",\n      \"method\": \"In vivo DNase I footprinting, dimethyl sulfate and UV-C footprinting, gel-shift (EMSA) assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo footprinting combined with EMSA in a single lab, two orthogonal methods with cell-type comparison\",\n      \"pmids\": [\"15705059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BDKRB1 activation in neutrophils during sepsis induces CXCR2 desensitization, impairing neutrophil migration. Genetic deletion of Bdkrb1 in mice subjected to cecal ligation and puncture (CLP) restored partial CXCR2 expression, reduced P110γ upregulation, increased peritoneal neutrophil influx, decreased bacterial load, and reduced lethality. In human neutrophils, BDKRB1 antagonism restored migration in response to CXCL8.\",\n      \"method\": \"Bdkrb1 knockout mice (CLP model), flow cytometry for CXCR2/P110γ, pharmacological BDKRB1 inhibition, human neutrophil migration assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined cellular phenotype corroborated by pharmacological inhibition and human neutrophil experiments, multiple orthogonal methods\",\n      \"pmids\": [\"41355798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mechanical stress (10% amplitude) upregulates BDKRB1 expression and activates a BDKRB1/Ca²⁺/CaMKII/MEK1/ERK signaling axis in alveolar epithelial cells (RLE-6TN), promoting cell proliferation and calcium influx. BDKRB1 knockdown attenuated both the growth and calcium influx increases induced by 10% mechanical stress and blocked activation of the downstream Ca²⁺/CaMKII/MEK1/ERK pathway.\",\n      \"method\": \"siRNA knockdown, RT-qPCR, western blotting, flow cytometry (calcium), CCK-8, EDU staining\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (knockdown) with defined pathway readout by western blot and functional assays, single lab\",\n      \"pmids\": [\"40296124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Transcription factor TFAP2A directly binds the BDKRB1 promoter and transcriptionally activates BDKRB1 expression, driving EMT progression in pulmonary fibrosis. TFAP2A knockdown reduced BDKRB1 RNA levels and protected against BLM-induced fibrosis, while BDKRB1 overexpression abrogated these protective effects.\",\n      \"method\": \"Promoter binding assay (TFAP2A ChIP/binding to BDKRB1 promoter), lentiviral knockdown, adenoviral shRNA, in vivo BLM mouse model, in vitro BEAS-2B cell assays, RT-PCR, western blot\",\n      \"journal\": \"Toxicology and applied pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding demonstrated with rescue (BDKRB1 overexpression reversal), single lab, multiple methods including in vivo and in vitro\",\n      \"pmids\": [\"41587695\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"METTL1-mediated N7-methylguanosine (m7G) modification stabilizes Bdkrb1 mRNA in epidermal keratinocytes, increasing BDKRB1 protein expression. Elevated BDKRB1 activates the p38 MAPK pathway, promoting secretion of CXCL chemokines and neutrophil chemotaxis in psoriasis. Keratinocyte-specific Mettl1 deletion attenuated psoriasiform inflammation and neutrophil infiltration, and both BDKRB1 overexpression and pharmacological BDKRB1 activation rescued this attenuated phenotype.\",\n      \"method\": \"Inducible keratinocyte-specific Mettl1 knockout mice (Mettl1fl/fl Krt14-CreERT2), m7G modification analysis, BDKRB1 overexpression rescue, pharmacological BDKRB1 activation, western blot, chemokine secretion assays, neutrophil chemotaxis assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with genetic rescue by BDKRB1 overexpression and pharmacological rescue, multiple orthogonal methods establishing the METTL1→m7G→Bdkrb1 mRNA stability→p38→CXCL→neutrophil axis\",\n      \"pmids\": [\"42261843\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"BDKRB1 (bradykinin B1 receptor) is a single-copy, inflammation-inducible GPCR whose transcription is driven by a 300-bp core promoter element (with a distal enhancer between -1842 and -812), regulated by YY1 and TBP/TFIIB, and directly transactivated by TFAP2A; at the post-transcriptional level, METTL1-mediated m7G modification stabilizes BDKRB1 mRNA; upon activation, BDKRB1 signals through Ca²⁺/CaMKII/MEK1/ERK to promote cell proliferation, activates p38 MAPK to drive CXCL chemokine secretion and neutrophil chemotaxis, and in neutrophils induces CXCR2 desensitization (via P110γ upregulation) to impair bacterial clearance during sepsis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"BDKRB1 (bradykinin B1 receptor) is an inflammation-inducible G-protein-coupled receptor that couples extracellular stimuli to pro-inflammatory and proliferative signaling, encoded by a single-copy gene whose expression is tightly transcriptionally controlled [#0, #2]. Its core promoter resides within a 300-bp fragment sufficient to drive reporter expression, with an additional enhancer-like element between -1842 and -812; the gene maps to chromosome 14q32.1-q32.2 near the B2 receptor gene [#1]. In cells that express the receptor, the core promoter is occupied by YY1 and the basal factors TBP/TFIIB, a pattern absent in non-expressing lymphocytes, and YY1 is implicated in NF-\\u03baB-linked regulation [#2]. BDKRB1 is further induced by the transcription factor TFAP2A, which binds the promoter directly and drives epithelial-mesenchymal transition in pulmonary fibrosis [#5], and is stabilized post-transcriptionally by METTL1-mediated m7G modification of its mRNA in keratinocytes [#6]. Once expressed, BDKRB1 transduces signals through distinct effector arms: a Ca\\u00b2\\u207a/CaMKII/MEK1/ERK axis that promotes calcium influx and cell proliferation in mechanically stressed alveolar epithelial cells [#4], and a p38 MAPK pathway that drives CXCL chemokine secretion and neutrophil chemotaxis in psoriatic inflammation [#6]. In sepsis, BDKRB1 activation in neutrophils induces CXCR2 desensitization with upregulation of P110\\u03b3, impairing neutrophil migration and bacterial clearance, such that Bdkrb1 deletion or antagonism restores migration and reduces lethality [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the genomic architecture and basal transcriptional landscape of BDKRB1, defining it as a single-copy gene whose coding region lies in a single exon under control of a TATA-box-containing promoter with multiple start sites.\",\n      \"evidence\": \"Genomic cloning, sequencing, and primer extension of the human gene\",\n      \"pmids\": [\n        \"8660997\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Did not identify the trans-acting factors controlling transcription\",\n        \"No functional dissection of the promoter elements\"\n      ]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Localized the cis-regulatory elements controlling BDKRB1, showing a 300-bp core promoter sufficient for expression plus a distal enhancer, and mapped the gene adjacent to the B2 receptor gene.\",\n      \"evidence\": \"CAT reporter deletion analysis and chromosomal localization\",\n      \"pmids\": [\n        \"8808279\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Did not identify which proteins bind these elements\",\n        \"Enhancer mechanism and tissue-specificity not resolved\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Connected cell-type-specific BDKRB1 expression to defined promoter occupancy, identifying YY1 and TBP/TFIIB as factors bound in expressing smooth muscle cells but not in non-expressing lymphocytes.\",\n      \"evidence\": \"In vivo DNase I/DMS/UV footprinting and EMSA in SMCs versus lymphocytes\",\n      \"pmids\": [\n        \"15705059\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"YY1 link to NF-\\u03baB regulation not directly demonstrated\",\n        \"No functional knockdown of YY1 to confirm requirement for expression\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a pathogenic role for BDKRB1 in sepsis by showing its activation desensitizes CXCR2 via P110\\u03b3 to block neutrophil migration and bacterial clearance.\",\n      \"evidence\": \"Bdkrb1 knockout mice in CLP model, flow cytometry, pharmacological inhibition, and human neutrophil migration assays\",\n      \"pmids\": [\n        \"41355798\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism linking BDKRB1 to P110\\u03b3 upregulation not resolved\",\n        \"Direct molecular coupling between BDKRB1 and CXCR2 desensitization unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified mechanical stress as an inducer of BDKRB1 and traced a downstream Ca\\u00b2\\u207a/CaMKII/MEK1/ERK axis driving epithelial proliferation.\",\n      \"evidence\": \"siRNA knockdown with western blot, calcium flow cytometry, and proliferation assays in alveolar epithelial cells\",\n      \"pmids\": [\n        \"40296124\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which mechanical stress upregulates BDKRB1 not defined\",\n        \"G-protein coupling linking receptor to calcium influx not characterized\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established TFAP2A as a direct transcriptional activator of BDKRB1 driving EMT in pulmonary fibrosis, with BDKRB1 acting downstream of TFAP2A.\",\n      \"evidence\": \"Promoter binding assay, lentiviral/adenoviral knockdown, BLM mouse model with BDKRB1 overexpression rescue\",\n      \"pmids\": [\n        \"41587695\"\n      ],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Signaling pathway linking BDKRB1 to EMT not detailed\",\n        \"Whether TFAP2A acts at the core promoter or enhancer not specified\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed post-transcriptional control of BDKRB1 by METTL1-mediated m7G mRNA modification and linked elevated BDKRB1 to p38-driven CXCL secretion and neutrophil recruitment in psoriasis.\",\n      \"evidence\": \"Keratinocyte-specific Mettl1 knockout mice with BDKRB1 overexpression and pharmacological rescue, m7G analysis, chemokine and chemotaxis assays\",\n      \"pmids\": [\n        \"42261843\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct demonstration of m7G sites on Bdkrb1 mRNA not detailed\",\n        \"Mechanism coupling BDKRB1 to p38 activation not resolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How BDKRB1 selects among its divergent downstream effector arms (Ca\\u00b2\\u207a/CaMKII/MEK1/ERK versus p38/CXCL versus CXCR2 desensitization) in a tissue- and stimulus-specific manner remains unknown.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural or G-protein-coupling data defining receptor signaling bias\",\n        \"Ligand-dependence of the distinct downstream pathways not dissected\",\n        \"No unified model of how transcriptional and post-transcriptional inputs converge on receptor output\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0060089\",\n        \"supporting_discovery_ids\": [\n          3,\n          4,\n          6\n        ]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005886\",\n        \"supporting_discovery_ids\": [\n          3,\n          4\n        ]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-162582\",\n        \"supporting_discovery_ids\": [\n          3,\n          4,\n          6\n        ]\n      },\n      {\n        \"term_id\": \"R-HSA-168256\",\n        \"supporting_discovery_ids\": [\n          3,\n          6\n        ]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}