Illuminating Orphan GPCRs in Lymphatics

阐明淋巴管中的孤儿 GPCR

• 批准号: 10216726
• 负责人: Kathleen M Caron
• 金额: $ 15.55万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216726
• 关键词: Accounting; Adult; American; Animal Model; Animals; Area; Arrestins; Bioinformatics; Biology; Categories; Cells; Clinical; Coupling; Cultured Cells; Data; Development; Drug Targeting; Dysplasia; Embryo; FAIRE sequencing; Fatty acid glycerol esters; Funding; Future; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Genetic; Genetic Engineering; Genome; Goals; Growth; Human; Human Development; Human Genome; Hydrops Fetalis; Immune; In Vitro; Individual; Intercellular Fluid; Knockout Mice; Knowledge; Laboratories; Learning; Ligands; Liquid substance; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic Diseases; Lymphatic Endothelial Cells; Lymphatic function; Lymphedema; Manuals; Massage; Medicine; Methods; Mission; Modeling; Modern Medicine; Molecular Chaperones; Molecular Target; Mus; Orphan; Pathway interactions; Pharmacology; Phenotype; Physiological; Protein Family; Proteins; Regulation; Reporter; Research; Research Proposals; Role; Series; Source; Study models; System; Technology; Testing; Therapeutic Agents; United States National Institutes of Health; absorption; adrenomedullin; base; calcitonin receptor-like receptor; compression therapy; human disease; in vivo; interest; loss of function mutation; lymphatic vasculature; lymphatic vessel; new therapeutic target; novel; receptor; recruit; response; spatiotemporal; therapeutic target; tool; trafficking; vascular bed

ABSTRACT Since more than 40% of all clinically-available drugs target G-protein coupled receptors (GPCRs), there is great interest in learning more about this family of proteins in order to discover new therapeutic targets. When considering the different classes of proteins encoded by the human genome that are predicted to be pharmacologically-tractable, a remarkable one quarter represent GPCRs. And yet, of the ~345 non-odorant GPCRs a large proportion remain orphan—with no known ligand—or have uncharacterized physiological functions. Since we have a dearth of pharmacological targets for lymphatic vessels, it stands to reason that focused efforts to explore and characterize the lymphatic “GPCRome” is a worthwhile endeavor. We have identified 3 orphan GPCRs that are IDG-eligible target proteins in the Illuminating the Druggable Genome (IDG) Project. We propose to develop and use in vitro and animal-based systems to further characterize the expression and activation of these GPCRs in the lymphatic vasculature. Our results will further the overall goals of the IDG Consortium and reveal novel physiological pathways and potential therapeutic targets for the modulation of lymphatics, which remains an understudied research area with unmet clinical needs.

摘要 由于超过40%的临床可用药物针对G蛋白偶联受体(GPCRs)， 人们非常有兴趣了解更多关于这个蛋白质家族的知识，以便发现新的 治疗靶点。当考虑到人类编码的不同类别的蛋白质时 预计在药物上容易处理的基因组中，有四分之一代表了 GPCRs。然而，在~345个无味GPCR中，很大一部分仍然是孤儿--没有 已知的配基-或具有未知的生理功能。因为我们缺少的是 淋巴管的药理靶点，顺理成章地集中精力探索 而将淋巴组织描述为“GPC罗马”是一项值得努力的工作。我们已经确认了3个 孤儿GPCRs是照亮可药物基因组中IDG合格的靶蛋白 (IDG)项目。我们建议开发和使用体外和基于动物的系统，以进一步 描述这些GPCRs在淋巴管系统中的表达和激活情况。我们的 结果将进一步推动IDG财团的总体目标，并揭示新的生理 调节淋巴管的途径和潜在的治疗靶点，它仍然是一种 研究不足、临床需求未得到满足的研究领域。