Metabolic Function of Gpr17 in Gastrointestinal Tract

项目摘要/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 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，以及外科手术 会带来并发症的风险。因此，迫切需要确定新的可用药靶点来有效地 治疗糖尿病和肥胖症。G蛋白偶联受体(GPCRs)调节重要生理功能 通过一系列不同的配体，是最成功的可用药靶标。因此，澄清 GPCRs在关键代谢器官中的生理功能为新药的开发提供了希望 代谢性疾病的治疗。近年来，胃肠道(GI)已成为一种新兴的 代谢性疾病治疗的治疗目标。胰岛素样物质，包括胰升糖素样肽1(GLP-1)和 葡萄糖依赖型促胰岛素多肽(GIP)是由肠内分泌细胞分泌的胃肠激素 在肠道中通过内分泌和神经机制调节葡萄糖代谢和能量平衡。这个 胰岛素激素的释放受到G蛋白偶联受体(GPCRs)及其同源物的严格调控 配基。然而，调节内源性胃肠激素分泌的途径并不完全清楚。我们 最近发现，GPR17在人类肠道中的GLP-1(但不是GIP)产生细胞中表达。这个 这项建议的总体目标是阐明Gpr17在胃肠道中的代谢功能。我们的初步数据 研究表明，肠道上皮细胞中Gpr17的缺失会导致葡萄糖耐量的改善，从而增加葡萄糖- 刺激胰岛素和GLP-1(但不是GIP)的分泌。Gpr17肠道基因敲除小鼠也表现出更高的饱腹感 在禁食-再喂食挑战中。根据我们的初步数据，我们假设抑制Gpr17的功能 在肠道中通过调节肠道内分泌细胞功能来改善血糖稳态和增加饱腹感 和肠道激素的释放。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 通过检测营养刺激的GLP-1等研究肠上皮细胞GPr17在血糖稳态中的作用 胃肠激素分泌和全身性胰岛素敏感性。在目标2中，我们将确定肠道Gpr17在 通过检测对肠道生理和迷走神经感觉系统的影响来调节饱腹感。在《目标3》中，我们将 Gpr17信号转导的功能特征及促进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行性 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Gpr17信号对全身糖代谢和饱腹感的代谢影响 监管。这些研究将为识别针对大脑肠道中Gpr17的新分子奠定基础 AXIS用于开发潜在的治疗方法。

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.