Metabolic Function of Gpr17 in Gastrointestinal Tract

项目总结/摘要 代谢性疾病，如糖尿病和肥胖症，影响着美国数百万人，导致糖尿病和肥胖症。 严重的发病率和死亡率。虽然密集的生活方式干预和减肥手术很常见， 治疗方法，生活方式干预通常不是长期持久的，外科手术 会有并发症的风险因此，迫切需要鉴定新的可药用靶标，以有效地治疗癌症。 治疗糖尿病和肥胖症。G蛋白偶联受体（GPCRs）调节重要的生理功能 通过不同的配体，并且是最成功的一类药物靶点。因此，阐明 GPCR在关键代谢器官中的生理功能有望开发新的 代谢性疾病的治疗剂。近年来，胃肠道（GI）已经成为一种新兴的疾病， 代谢性疾病治疗的治疗靶点。肠促胰岛素，包括胰高血糖素样肽1（GLP-1）和 葡萄糖依赖性促胰岛素多肽（GIP）是由肠内分泌细胞分泌的肠道激素 通过内分泌和神经机制调节葡萄糖代谢和能量平衡。的 肠促胰岛素激素的释放受G蛋白偶联受体（GPCR）及其同源物的严格调节 配体。然而，调节内源性肠道激素分泌的途径尚未完全了解。我们 最近发现GPR 17在人肠道中的GLP-1（而不是GIP）产生细胞中表达。的 该提议的总体目标是阐明Gpr 17在胃肠道中的代谢功能。我们的初步数据 显示肠道上皮中Gpr 17的缺失导致葡萄糖耐量的改善， 刺激胰岛素和GLP-1（但不是GIP）分泌。gpr 17肠敲除小鼠也表现出增加的饱腹感 在禁食再喂养激发期间。基于我们的初步数据，我们假设抑制Gpr 17功能 通过调节肠内分泌细胞功能改善葡萄糖稳态并增加饱腹感 和肠道激素释放。为了验证我们的假设，我们提出了以下研究。在目标1中，我们将确定 肠上皮Gpr 17在葡萄糖稳态中作用--通过测量营养素刺激的GLP-1和其他 肠激素分泌和全身胰岛素敏感性。在目标2中，我们将确定肠Gpr 17在 通过检查对肠道生理学和迷走神经感觉系统的影响来调节饱腹感。在目标3中，我们 在功能上表征Gpr 17信号传导并鉴定增强GLP-1分泌的分子机制， 肠内分泌细胞我们的初步数据和体外和体内模型的可用性 支持我们建议的研究的可行性。在成功完成这项建议后，我们预计 确定肠道中Gpr 17信号传导对全身葡萄糖代谢和饱腹感的代谢作用 调控这些研究将为识别脑肠道中靶向Gpr 17的新分子奠定基础。 潜在治疗方法的发展轴。

PROJECT SUMMARY/ABSTRACT Metabolic diseases, such as diabetes and obesity, affect millions of individuals in the United States leading to significant morbidity and mortality. While intensive lifestyle intervention and bariatric surgery are common treatment approaches, lifestyle intervention is not typically durable in the long term, and surgical procedures carry the risk of complications. Hence, there is a critical need to identify novel druggable targets to effectively treat diabetes and obesity. G protein–coupled receptors (GPCRs) regulate important physiological functions through a diverse array of ligands and are the most successful class of druggable targets. Therefore, elucidating the physiological function of GPCRs in key metabolic organs holds promise to the development of novel therapeutics for metabolic diseases. In recent years, gastrointestinal (GI) tract has become an emerging therapeutic target for metabolic disease therapy. Incretins, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are gut hormones secreted by the enteroendocrine cells in the gut to regulate glucose metabolism and energy balance via endocrine and neural mechanisms. The release of incretin hormones is tightly regulated by G protein-coupled receptors (GPCRs) and their cognate ligands. However, pathways regulating endogenous gut hormone secretion are not completely understood. We recently discovered that GPR17 is expressed in the GLP-1 (but not GIP)-producing cells in human gut. The overall goal of this proposal is to elucidate the metabolic function of Gpr17 in the GI tract. Our preliminary data showed that loss of Gpr17 in gut epithelium leads to improved glucose tolerance with increased glucose- stimulated insulin and GLP-1 (but not GIP) secretion. Gpr17 gut knockout mice also exhibit increased satiety during fasting-refeeding challenge. Based on our preliminary data, we hypothesize that inhibiting Gpr17 function in the gut improves glucose homeostasis and increases satiety via modulating enteroendocrine cellular function and gut hormone release. To test our hypothesis, we propose the following studies. In Aim 1, we will determine the role of intestinal epithelial Gpr17 in glucose homeostasis by measuring nutrient-stimulated GLP-1 and other gut hormone secretion and systemic insulin sensitivity. In Aim 2, we will determine the role of intestinal Gpr17 in satiety regulation by examining the effects on gut physiology and vagal sensory system. In Aim 3, we will functionally characterize Gpr17 signaling and identify molecular mechanisms to potentiate GLP-1 secretion in enteroendocrine cells. Our preliminary data and the demonstrated availability of in vitro and in vivo models support the feasibility of our proposed study. Upon successful completion of this proposal, we expect to determine the metabolic effect of Gpr17 signaling in the gut on systemic glucose metabolism and satiety regulation. These studies will lay the foundation for identifying novel molecules that target Gpr17 in the brain-gut axis for the development of potential therapeutic approaches.