{"gene":"PTGDR","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2011,"finding":"The PTGDR promoter polymorphism -613C>T alters transcription factor binding affinity, as demonstrated by electrophoretic mobility shift assays (EMSAs) with different promoter variants. Methylation analysis also revealed differences in methylation patterns between asthmatic patients and controls, with asthmatic patients showing a 2.34-fold increase in PTGDR expression.","method":"Electrophoretic mobility shift assay (EMSA), MassArray epigenetic analysis, real-time PCR expression analysis","journal":"Allergy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct EMSA demonstrating altered transcription factor binding, supported by methylation and expression data in a single lab study","pmids":["21883277"],"is_preprint":false},{"year":2014,"finding":"PTGDR (DP1) mediates tumor suppression by prostaglandin D2 (PGD2) in the intestine; homozygous Ptgdr knockout in ApcMin/+ mice raised total intestinal tumor numbers by 30–40% at 6 and 14 weeks, while colon tumors were unaffected. The suppression mechanism did not involve changes in microvessel density or tumor cell proliferation rate.","method":"Genetic knockout mouse model (Ptgdr knockout in ApcMin/+ background), tumor counting, MYC mRNA measurement","journal":"Cancer medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean in vivo knockout with defined tumor phenotype in multiple cohorts (147 mice), with negative controls ruling out two alternative mechanisms","pmids":["24729479"],"is_preprint":false},{"year":2016,"finding":"Retinoic acid (RA) activates PTGDR promoter activity in a haplotype-dependent manner. ATRA treatment of A549 lung epithelial cells transfected with PTGDR promoter variants increased promoter activity (p<0.001), and RA response element (RARE) sequences were identified in silico in the PTGDR promoter region. ATRA also induced upregulation of CYP26A1 (12-fold) and RARB (4-fold).","method":"Luciferase reporter assay in transfected A549 cells, real-time qPCR, in silico RARE analysis","journal":"Journal of investigational allergology & clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional luciferase assay with genetic variants in a single lab, single study","pmids":["27373883"],"is_preprint":false},{"year":2019,"finding":"PTGDR expression is upregulated by all-trans retinoic acid (ATRA) primarily through RARα binding to RARE sequences in the PTGDR promoter, in a haplotype-dependent manner: the CTCT (-549T) variant showed stronger RARα-mediated induction than the CCCC variant. ChIP assays confirmed RARα binding to the PTGDR promoter. PTGDR overexpression in A549 cells increased IL-4 and IL-6 secretion, while ATRA treatment modulated these cytokine levels.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, qPCR, cytometric bead array for cytokines, ATRA/RAR antagonist treatment in PBMCs from allergic patients","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms RARα binding to PTGDR promoter, supported by functional reporter assays and cytokine measurements, single lab with multiple orthogonal methods","pmids":["30986261"],"is_preprint":false},{"year":2018,"finding":"PTGDR is a direct target gene of miR-592-5p; knockdown of PTGDR (siRNA) or overexpression of miR-592-5p mimics in hippocampal neuronal cells subjected to hypoxic-ischemic conditions decreased PTGDR, DP2, and Bax expression while increasing Bcl-2 expression, prolonged S phase, increased proliferation, and reduced apoptosis. Inhibition of miR-592-5p had opposite effects.","method":"siRNA knockdown, miRNA mimic/inhibitor transfection, RT-qPCR, Western blot, MTT assay, flow cytometry in mouse hippocampal neuronal cell model","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct siRNA-PTGDR knockdown with defined cellular phenotypes mirroring miR-592-5p overexpression, multiple readouts, single lab","pmids":["29402808"],"is_preprint":false}],"current_model":"PTGDR (prostanoid DP1 receptor) is a G protein-coupled receptor for prostaglandin D2 that suppresses intestinal tumor formation in vivo, modulates neuronal apoptosis and proliferation downstream of the PGD2/DP signaling pathway, is transcriptionally regulated by retinoic acid through RARα binding to promoter RARE sequences in a haplotype-dependent manner, and has promoter activity further modulated by DNA methylation and transcription factor binding influenced by functional SNPs."},"narrative":{"mechanistic_narrative":"PTGDR encodes the prostanoid DP1 receptor, a G protein-coupled receptor for prostaglandin D2 that acts as a tumor suppressor in the intestine: homozygous Ptgdr loss in ApcMin/+ mice raised intestinal tumor numbers by 30–40% without altering microvessel density or tumor cell proliferation, indicating a suppressive role independent of angiogenesis and proliferative rate [PMID:24729479]. In a neuronal context, PTGDR participates in the control of cell survival and proliferation, where its knockdown shifts hippocampal neuronal cells toward reduced apoptosis (lower Bax, higher Bcl-2) and increased proliferation, placing it as a direct downstream target of miR-592-5p under hypoxic-ischemic conditions [PMID:29402808]. Much of the characterized biology concerns transcriptional control of the gene rather than its receptor signaling: PTGDR expression is induced by all-trans retinoic acid through RARα binding to RARE sequences in the promoter in a haplotype-dependent manner, with the CTCT (-549T) variant showing stronger induction than CCCC, and ATRA-driven PTGDR overexpression altering IL-4 and IL-6 secretion [PMID:27373883, PMID:30986261]. Promoter function is further shaped by the -613C>T polymorphism, which alters transcription factor binding affinity, and by differential DNA methylation associated with elevated expression in asthmatic patients [PMID:21883277]. The receptor's own downstream G protein signaling and ligand-binding mechanism are not characterized in the available corpus.","teleology":[{"year":2011,"claim":"Established that common PTGDR promoter variation and epigenetic state, not just coding sequence, govern its expression level, linking the gene to inflammatory disease risk.","evidence":"EMSA of promoter variants plus methylation and expression profiling in asthmatic patients versus controls","pmids":["21883277"],"confidence":"Medium","gaps":["The specific transcription factor binding differentially to the -613C/T allele was not identified","Causal link between methylation change and the 2.34-fold expression increase not established","Does not address receptor signaling output"]},{"year":2014,"claim":"Demonstrated that the DP1 receptor mediates PGD2-driven tumor suppression in vivo, defining a protective function in intestinal tumorigenesis.","evidence":"Ptgdr knockout in ApcMin/+ mice with tumor counting and MYC mRNA measurement across multiple cohorts","pmids":["24729479"],"confidence":"High","gaps":["Mechanism of suppression unresolved — proliferation and microvessel density were ruled out","Colon tumors were unaffected, leaving tissue specificity unexplained","Downstream G protein effectors not identified"]},{"year":2016,"claim":"Showed that retinoic acid activates the PTGDR promoter in a haplotype-dependent manner, connecting RA signaling to PTGDR transcriptional control.","evidence":"Luciferase reporter assays of promoter variants in ATRA-treated A549 cells with in silico RARE identification","pmids":["27373883"],"confidence":"Medium","gaps":["Direct RAR binding not demonstrated in this study (in silico RARE only)","Physiological relevance of A549 reporter activity to native PTGDR locus unclear"]},{"year":2019,"claim":"Identified RARα as the direct transcriptional activator binding the PTGDR promoter and linked PTGDR levels to cytokine output, mechanistically grounding the RA-haplotype relationship.","evidence":"ChIP confirming RARα promoter binding, luciferase reporters, and cytokine bead arrays in patient PBMCs with ATRA/RAR antagonist treatment","pmids":["30986261"],"confidence":"Medium","gaps":["Mechanism by which haplotype alters RARα binding affinity not resolved","Causal chain from PTGDR level to IL-4/IL-6 secretion not dissected","Receptor signaling downstream of PGD2 not addressed"]},{"year":2018,"claim":"Placed PTGDR downstream of miR-592-5p as a regulator of neuronal apoptosis and proliferation under hypoxic-ischemic stress, extending its role beyond inflammation and tumor biology.","evidence":"siRNA knockdown and miR-592-5p mimic/inhibitor transfection with apoptosis, cell-cycle, and proliferation readouts in mouse hippocampal neuronal cells","pmids":["29402808"],"confidence":"Medium","gaps":["Direct miR-592-5p:PTGDR target interaction shown phenotypically but binding-site validation not detailed","Signaling pathway linking PTGDR to Bax/Bcl-2 regulation not defined","In vivo neuronal relevance not tested"]},{"year":null,"claim":"How the DP1 receptor transduces the PGD2 signal — its G protein coupling, second messengers, and the molecular link to its tumor-suppressive and apoptotic outputs — remains uncharacterized in the available corpus.","evidence":"No discovery in the timeline addresses receptor-level signaling mechanism","pmids":[],"confidence":"Low","gaps":["No ligand-binding or G protein coupling data","No structural model","Downstream effectors of tumor suppression unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13258","full_name":"Prostaglandin D2 receptor","aliases":["Prostanoid DP receptor"],"length_aa":359,"mass_kda":40.3,"function":"Receptor for prostaglandin D2 (PGD2). The activity of this receptor is mainly mediated by G(s) proteins that stimulate adenylate cyclase, resulting in an elevation of intracellular cAMP. A mobilization of calcium is also observed, but without formation of inositol 1,4,5-trisphosphate (By similarity). Involved in PLA2G3-dependent maturation of mast cells. PLA2G3 is secreted by immature mast cells and acts on nearby fibroblasts upstream to PTDGS to synthesize PGD2, which in turn promotes mast cell maturation and degranulation via PTGDR (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q13258/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTGDR","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTGDR","total_profiled":1310},"omim":[{"mim_id":"615125","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 13C; ANKRD13C","url":"https://www.omim.org/entry/615125"},{"mim_id":"607277","title":"ASTHMA-RELATED TRAITS, SUSCEPTIBILITY TO, 1","url":"https://www.omim.org/entry/607277"},{"mim_id":"604837","title":"PROSTAGLANDIN D2 RECEPTOR 2; PTGDR2","url":"https://www.omim.org/entry/604837"},{"mim_id":"604687","title":"PROSTAGLANDIN D2 RECEPTOR; PTGDR","url":"https://www.omim.org/entry/604687"},{"mim_id":"601487","title":"PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA; PPARG","url":"https://www.omim.org/entry/601487"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":7.4},{"tissue":"lymphoid tissue","ntpm":5.9}],"url":"https://www.proteinatlas.org/search/PTGDR"},"hgnc":{"alias_symbol":["DP","DP1","PTGDR1"],"prev_symbol":[]},"alphafold":{"accession":"Q13258","domains":[{"cath_id":"1.20.1070.10","chopping":"21-48_57-234_263-327","consensus_level":"high","plddt":87.8183,"start":21,"end":327}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13258","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13258-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13258-F1-predicted_aligned_error_v6.png","plddt_mean":79.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTGDR","jax_strain_url":"https://www.jax.org/strain/search?query=PTGDR"},"sequence":{"accession":"Q13258","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13258.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13258/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13258"}},"corpus_meta":[{"pmid":"26482433","id":"PMC_26482433","title":"DNA hypermethylation and decreased mRNA expression of MAL, PRIMA1, PTGDR and SFRP1 in colorectal adenoma and cancer.","date":"2015","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26482433","citation_count":51,"is_preprint":false},{"pmid":"21883277","id":"PMC_21883277","title":"PTGDR gene in asthma: a functional, genetic, and epigenetic study.","date":"2011","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/21883277","citation_count":39,"is_preprint":false},{"pmid":"16629782","id":"PMC_16629782","title":"Promoter genetic variants of prostanoid DP receptor (PTGDR) gene in patients with asthma.","date":"2006","source":"Allergy","url":"https://pubmed.ncbi.nlm.nih.gov/16629782","citation_count":29,"is_preprint":false},{"pmid":"29402808","id":"PMC_29402808","title":"Effects of MicroRNA-592-5p on Hippocampal Neuron Injury Following Hypoxic-Ischemic Brain Damage in Neonatal Mice - Involvement of PGD2/DP and PTGDR.","date":"2018","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29402808","citation_count":23,"is_preprint":false},{"pmid":"17157653","id":"PMC_17157653","title":"The PTGDR gene is not associated with asthma in 3 ethnically diverse populations.","date":"2006","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/17157653","citation_count":22,"is_preprint":false},{"pmid":"17538632","id":"PMC_17538632","title":"Association of PTGDR gene polymorphisms with asthma in two Caucasian populations.","date":"2007","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/17538632","citation_count":21,"is_preprint":false},{"pmid":"23410912","id":"PMC_23410912","title":"The prostaglandin D2 receptor (PTGDR) gene in asthma and allergic diseases.","date":"2013","source":"Allergologia et immunopathologia","url":"https://pubmed.ncbi.nlm.nih.gov/23410912","citation_count":17,"is_preprint":false},{"pmid":"21307858","id":"PMC_21307858","title":"Polymorphisms of the PTGDR and LTC4S influence responsiveness to leukotriene receptor antagonists in Korean children with asthma.","date":"2011","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21307858","citation_count":17,"is_preprint":false},{"pmid":"24729479","id":"PMC_24729479","title":"Intestinal tumor suppression in ApcMin/+ mice by prostaglandin D2 receptor PTGDR.","date":"2014","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24729479","citation_count":15,"is_preprint":false},{"pmid":"18811623","id":"PMC_18811623","title":"A new PTGDR promoter polymorphism in a population of children with asthma.","date":"2008","source":"Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18811623","citation_count":12,"is_preprint":false},{"pmid":"33003642","id":"PMC_33003642","title":"G Protein-Coupled Receptor Genes, PTGDR1, PTGDR2, and PTGIR, Are Candidate Epigenetic Biomarkers and Predictors for Treated Patients with HPV-Associated Oropharyngeal Cancer.","date":"2020","source":"Microorganisms","url":"https://pubmed.ncbi.nlm.nih.gov/33003642","citation_count":11,"is_preprint":false},{"pmid":"17845306","id":"PMC_17845306","title":"Lack of association between three promoter polymorphisms of PTGDR gene and asthma in a Chinese Han population.","date":"2007","source":"International journal of immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/17845306","citation_count":11,"is_preprint":false},{"pmid":"19220773","id":"PMC_19220773","title":"PTGDR is not a major candidate gene for asthma and atopy in Chinese children.","date":"2009","source":"Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/19220773","citation_count":10,"is_preprint":false},{"pmid":"21199159","id":"PMC_21199159","title":"Functional haplotypes in the PTGDR gene fail to associate with asthma in two Australian populations.","date":"2011","source":"Respirology (Carlton, Vic.)","url":"https://pubmed.ncbi.nlm.nih.gov/21199159","citation_count":8,"is_preprint":false},{"pmid":"31062691","id":"PMC_31062691","title":"Promoter Genotyping and mRNA Expression - Based Analysis of the PTGDR Gene in Allergy.","date":"2019","source":"Journal of investigational allergology & clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31062691","citation_count":5,"is_preprint":false},{"pmid":"19710676","id":"PMC_19710676","title":"Prostanoid DP receptor (PTGDR) variants in mothers with post-coital associated preterm births: preliminary observations.","date":"2009","source":"Journal of perinatology : official journal of the California Perinatal Association","url":"https://pubmed.ncbi.nlm.nih.gov/19710676","citation_count":5,"is_preprint":false},{"pmid":"23192614","id":"PMC_23192614","title":"PTGDR polymorphisms and susceptibility to asthma: a meta-analysis.","date":"2012","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23192614","citation_count":4,"is_preprint":false},{"pmid":"30986261","id":"PMC_30986261","title":"PTGDR expression is upregulated through retinoic acid receptors (RAR) mechanism in allergy.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30986261","citation_count":4,"is_preprint":false},{"pmid":"27373883","id":"PMC_27373883","title":"Retinoic Acid Modulates PTGDR Promoter Activity.","date":"2016","source":"Journal of investigational allergology & clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/27373883","citation_count":3,"is_preprint":false},{"pmid":"22182808","id":"PMC_22182808","title":"No association of PTGDR -441C/T polymorphism with asthma in a North Indian population.","date":"2011","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/22182808","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13349,"output_tokens":1461,"usd":0.030981,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8204,"output_tokens":2238,"usd":0.048485,"stage2_stop_reason":"end_turn"},"total_usd":0.079466,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"The PTGDR promoter polymorphism -613C>T alters transcription factor binding affinity, as demonstrated by electrophoretic mobility shift assays (EMSAs) with different promoter variants. Methylation analysis also revealed differences in methylation patterns between asthmatic patients and controls, with asthmatic patients showing a 2.34-fold increase in PTGDR expression.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), MassArray epigenetic analysis, real-time PCR expression analysis\",\n      \"journal\": \"Allergy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct EMSA demonstrating altered transcription factor binding, supported by methylation and expression data in a single lab study\",\n      \"pmids\": [\"21883277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTGDR (DP1) mediates tumor suppression by prostaglandin D2 (PGD2) in the intestine; homozygous Ptgdr knockout in ApcMin/+ mice raised total intestinal tumor numbers by 30–40% at 6 and 14 weeks, while colon tumors were unaffected. The suppression mechanism did not involve changes in microvessel density or tumor cell proliferation rate.\",\n      \"method\": \"Genetic knockout mouse model (Ptgdr knockout in ApcMin/+ background), tumor counting, MYC mRNA measurement\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo knockout with defined tumor phenotype in multiple cohorts (147 mice), with negative controls ruling out two alternative mechanisms\",\n      \"pmids\": [\"24729479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Retinoic acid (RA) activates PTGDR promoter activity in a haplotype-dependent manner. ATRA treatment of A549 lung epithelial cells transfected with PTGDR promoter variants increased promoter activity (p<0.001), and RA response element (RARE) sequences were identified in silico in the PTGDR promoter region. ATRA also induced upregulation of CYP26A1 (12-fold) and RARB (4-fold).\",\n      \"method\": \"Luciferase reporter assay in transfected A549 cells, real-time qPCR, in silico RARE analysis\",\n      \"journal\": \"Journal of investigational allergology & clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional luciferase assay with genetic variants in a single lab, single study\",\n      \"pmids\": [\"27373883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTGDR expression is upregulated by all-trans retinoic acid (ATRA) primarily through RARα binding to RARE sequences in the PTGDR promoter, in a haplotype-dependent manner: the CTCT (-549T) variant showed stronger RARα-mediated induction than the CCCC variant. ChIP assays confirmed RARα binding to the PTGDR promoter. PTGDR overexpression in A549 cells increased IL-4 and IL-6 secretion, while ATRA treatment modulated these cytokine levels.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, qPCR, cytometric bead array for cytokines, ATRA/RAR antagonist treatment in PBMCs from allergic patients\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms RARα binding to PTGDR promoter, supported by functional reporter assays and cytokine measurements, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30986261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTGDR is a direct target gene of miR-592-5p; knockdown of PTGDR (siRNA) or overexpression of miR-592-5p mimics in hippocampal neuronal cells subjected to hypoxic-ischemic conditions decreased PTGDR, DP2, and Bax expression while increasing Bcl-2 expression, prolonged S phase, increased proliferation, and reduced apoptosis. Inhibition of miR-592-5p had opposite effects.\",\n      \"method\": \"siRNA knockdown, miRNA mimic/inhibitor transfection, RT-qPCR, Western blot, MTT assay, flow cytometry in mouse hippocampal neuronal cell model\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct siRNA-PTGDR knockdown with defined cellular phenotypes mirroring miR-592-5p overexpression, multiple readouts, single lab\",\n      \"pmids\": [\"29402808\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTGDR (prostanoid DP1 receptor) is a G protein-coupled receptor for prostaglandin D2 that suppresses intestinal tumor formation in vivo, modulates neuronal apoptosis and proliferation downstream of the PGD2/DP signaling pathway, is transcriptionally regulated by retinoic acid through RARα binding to promoter RARE sequences in a haplotype-dependent manner, and has promoter activity further modulated by DNA methylation and transcription factor binding influenced by functional SNPs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTGDR encodes the prostanoid DP1 receptor, a G protein-coupled receptor for prostaglandin D2 that acts as a tumor suppressor in the intestine: homozygous Ptgdr loss in ApcMin/+ mice raised intestinal tumor numbers by 30–40% without altering microvessel density or tumor cell proliferation, indicating a suppressive role independent of angiogenesis and proliferative rate [#1]. In a neuronal context, PTGDR participates in the control of cell survival and proliferation, where its knockdown shifts hippocampal neuronal cells toward reduced apoptosis (lower Bax, higher Bcl-2) and increased proliferation, placing it as a direct downstream target of miR-592-5p under hypoxic-ischemic conditions [#4]. Much of the characterized biology concerns transcriptional control of the gene rather than its receptor signaling: PTGDR expression is induced by all-trans retinoic acid through RARα binding to RARE sequences in the promoter in a haplotype-dependent manner, with the CTCT (-549T) variant showing stronger induction than CCCC, and ATRA-driven PTGDR overexpression altering IL-4 and IL-6 secretion [#2, #3]. Promoter function is further shaped by the -613C>T polymorphism, which alters transcription factor binding affinity, and by differential DNA methylation associated with elevated expression in asthmatic patients [#0]. The receptor's own downstream G protein signaling and ligand-binding mechanism are not characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that common PTGDR promoter variation and epigenetic state, not just coding sequence, govern its expression level, linking the gene to inflammatory disease risk.\",\n      \"evidence\": \"EMSA of promoter variants plus methylation and expression profiling in asthmatic patients versus controls\",\n      \"pmids\": [\"21883277\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The specific transcription factor binding differentially to the -613C/T allele was not identified\",\n        \"Causal link between methylation change and the 2.34-fold expression increase not established\",\n        \"Does not address receptor signaling output\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated that the DP1 receptor mediates PGD2-driven tumor suppression in vivo, defining a protective function in intestinal tumorigenesis.\",\n      \"evidence\": \"Ptgdr knockout in ApcMin/+ mice with tumor counting and MYC mRNA measurement across multiple cohorts\",\n      \"pmids\": [\"24729479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of suppression unresolved — proliferation and microvessel density were ruled out\",\n        \"Colon tumors were unaffected, leaving tissue specificity unexplained\",\n        \"Downstream G protein effectors not identified\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed that retinoic acid activates the PTGDR promoter in a haplotype-dependent manner, connecting RA signaling to PTGDR transcriptional control.\",\n      \"evidence\": \"Luciferase reporter assays of promoter variants in ATRA-treated A549 cells with in silico RARE identification\",\n      \"pmids\": [\"27373883\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct RAR binding not demonstrated in this study (in silico RARE only)\",\n        \"Physiological relevance of A549 reporter activity to native PTGDR locus unclear\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified RARα as the direct transcriptional activator binding the PTGDR promoter and linked PTGDR levels to cytokine output, mechanistically grounding the RA-haplotype relationship.\",\n      \"evidence\": \"ChIP confirming RARα promoter binding, luciferase reporters, and cytokine bead arrays in patient PBMCs with ATRA/RAR antagonist treatment\",\n      \"pmids\": [\"30986261\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which haplotype alters RARα binding affinity not resolved\",\n        \"Causal chain from PTGDR level to IL-4/IL-6 secretion not dissected\",\n        \"Receptor signaling downstream of PGD2 not addressed\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed PTGDR downstream of miR-592-5p as a regulator of neuronal apoptosis and proliferation under hypoxic-ischemic stress, extending its role beyond inflammation and tumor biology.\",\n      \"evidence\": \"siRNA knockdown and miR-592-5p mimic/inhibitor transfection with apoptosis, cell-cycle, and proliferation readouts in mouse hippocampal neuronal cells\",\n      \"pmids\": [\"29402808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct miR-592-5p:PTGDR target interaction shown phenotypically but binding-site validation not detailed\",\n        \"Signaling pathway linking PTGDR to Bax/Bcl-2 regulation not defined\",\n        \"In vivo neuronal relevance not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the DP1 receptor transduces the PGD2 signal — its G protein coupling, second messengers, and the molecular link to its tumor-suppressive and apoptotic outputs — remains uncharacterized in the available corpus.\",\n      \"evidence\": \"No discovery in the timeline addresses receptor-level signaling mechanism\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No ligand-binding or G protein coupling data\",\n        \"No structural model\",\n        \"Downstream effectors of tumor suppression unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}