GPCR-mediated pathways for regulation of intestinal lymphatic function

摘要 G蛋白偶联受体（GPCR）代表了最大的一类药理学靶点， 现代药物，占全球所有处方的60%以上。然而，在345个非- 嗅觉GPCR，许多仍然是孤儿（没有已知的配体）或未表征（没有明确的 生理功能）。因此，揭示GPCR的时空调控和功能， 在药学上和生理学上未充分研究的系统中的药物代谢具有重要的临床意义。 考虑到淋巴管在肠道脂质吸收中的重要作用和增加的 肠道炎症和代谢性疾病的患病率，相当值得注意的是， 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，本研究中提出的 补助金的目的是解决最近提出的许多关键问题， NIH/NIDDK申办的RFA-DK-17-016，标题为：健康和消化系统疾病中的淋巴管 系统利用最先进的生物化学、蛋白质组学、基因组学和动物模型方法， 我建议建立在我们目前对淋巴管内CLR-AM信号轴的专业知识基础上， 系统最终，我们希望我们的研究将扩大GPCR途径的全部功能， 在胃肠道内神经淋巴分泌单位的调节中起重要作用， 发现独特的和药理学上易于处理的途径，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.