GPCR-mediated pathways for regulation of intestinal lymphatic function

摘要 G蛋白偶联受体(GPCRs)是一类最大的药理靶点 现代医学，占全球处方总数的60%以上。然而，在~345名非 嗅觉GPCRs，许多要么是孤儿(没有已知的配体)，要么是没有特征的(没有明确的 生理功能)。因此，发现GPCRs的时空调节和功能 在药理学和生理学研究不足的系统中具有重要的临床意义。 考虑到淋巴管在肠道脂肪吸收中的重要作用和增加 肠炎性和代谢性疾病的流行，相当值得注意的是 目前更多的是关于淋巴管是否和/或如何 有助于成人的正常消化功能和/或疾病。因此，在此提出的研究 Grant被有目的地设计来解决最近 NIH/NIDDK赞助的RFA-DK-17-016，题为：消化系统中的淋巴管 系统。使用最先进的生化、蛋白质组、基因组和动物模型方法，我们 建议以我们目前在淋巴管内CLR-AM信号轴方面的专业知识为基础 系统。最终，我们希望我们的研究将扩大gpr途径发挥作用的曲目。 在胃肠道内神经淋巴分泌单位的调节中的重要作用，并潜在地 发现独特的和药理上易于处理的途径，以改善消化健康。

Abstract G protein-coupled receptors (GPCRs) represent the largest class of pharmacological targets in modern medicine, accounting for over 60% of all prescriptions worldwide. Yet, of the ~345 non- olfactory GPCRs, many remain either orphan (with no known ligand) or uncharacterized (with no clear physiological function). Therefore, discovering the spatiotemporal regulation and function of GPCRs within pharmaceutically- and physiologically-understudied systems is of great clinical importance. Considering the essential role of lymphatic vessels in intestinal lipid absorption and the increased prevalence of inflammatory and metabolic diseases of the intestine, it is rather remarkable that there are currently more questions than answers regarding whether and/or how lymphatic vessels contribute to normal digestive function and/or diseases in adults. Therefore, studies proposed in this grant have been purposefully designed to address numerous key questions raised by the recent NIH/NIDDK-sponsored RFA-DK-17-016 entitled: Lymphatics in Health and Disease in the Digestive System. Using state-of-the-art biochemical, proteomic, genomic and animal model approaches, we propose to build on our current expertise on the CLR-AM signaling axis within the lymphatic vascular system. Ultimately, we hope our studies will expand the repertoire of GPCR pathways that play important functions in the regulation of the neurolymphocrine unit within the GI tract, and potentially uncover unique and pharmacologically-tractable pathways for the improvement of digestive health.