Metabolic Function of Gpr17 in Gastrointestinal Tract

Gpr17在胃肠道中的代谢功能

基本信息

批准号：
10077839
负责人：
Hongxia Ren
金额：
$ 40.12万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10077839
关键词：
Address Affect Agonist Appetite Stimulants Behavior Body Composition Body Weight Brain Calcium Cell physiology Cells Cellular Assay Chronic Disease Closure by clamp Couples Cyclic AMP Data Development Diabetes Mellitus Endocrine Enteroendocrine Cell Exhibits Fasting Food Foundations Future G-Protein-Coupled Receptors GPR17 gene GTP-Binding Protein alpha Subunits, Gs Gastrointestinal tract structure Glucose Goals Graph Hormone secretion Hormones Human In Vitro Individual Ingestion Insulin Intestines Knock-out Knockout Mice Ligands Light Measures Mediating Mediator of activation protein Metabolic Metabolic Diseases Modeling Molecular Morbidity - disease rate Mus Nutrient Obesity Operative Surgical Procedures Organ Organoids Orphan Pathway interactions Pattern Pertussis Toxin Phenotype Physiological Physiology Production Regulation Resolution Risk Rodent Role Satiation Signal Transduction Stimulus Stomach Testing Therapeutic Tissues United States Work bariatric surgery base blood glucose regulation cell motility common treatment cost detection of nutrient druggable target energy balance feeding gastric inhibitory polypeptide receptor gastrointestinal gastrointestinal epithelium glucagon-like peptide 1 glucose metabolism glucose tolerance gut-brain axis imaging system improved in vivo Model incretin hormone insulin sensitivity insulin signaling insulin tolerance intestinal epithelium lifestyle intervention live cell imaging mortality mouse model neuromechanism new therapeutic target novel novel therapeutics reduced food intake response sensory system spatiotemporal therapeutic target

项目摘要

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.

项目概要/摘要糖尿病和肥胖等代谢疾病影响着美国数百万人，导致显着的发病率和死亡率，而强化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会长期持久，而且外科手术因此，迫切需要确定新的可药物靶标以有效地进行治疗。治疗糖尿病和肥胖症。G蛋白偶联受体（GPCR）调节重要的生理功能。通过多种配体，是最成功的一类可药物靶标。 GPCR 在关键代谢器官中的生理功能有望开发新的近年来，胃肠道（GI）疾病的治疗已成为一种新兴的治疗方法。代谢性疾病治疗的治疗靶点，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）是肠内分泌细胞分泌的肠道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。肠促胰岛素激素的释放受到 G 蛋白偶联受体 (GPCR) 及其同源物的严格调节然而，我们尚未完全了解调节内源性肠道激素分泌的途径。最近发现 GPR17 在人类肠道中产生 GLP-1（但不包括 GIP）的细胞中表达。该提案的总体目标是阐明 Gpr17 在胃肠道中的代谢功能。研究表明，肠上皮细胞中 Gpr17 的缺失会导致糖耐量的改善，同时葡萄糖的增加刺激胰岛素和 GLP-1（但不是 GIP）分泌 Gpr17 肠道基因敲除小鼠也表现出饱腹感增加。在禁食-再进食挑战期间，根据我们的初步数据，我们参与了抑制 Gpr17 功能的研究。在肠道中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为了检验我们的假设，我们在目标 1 中提出了以下研究：通过测量营养刺激的 GLP-1 等来研究肠上皮 Gpr17 在葡萄糖稳态中的作用在目标 2 中，我们将确定肠道 Gpr17 在肠道激素分泌和全身胰岛素敏感性中的作用。在目标 3 中，我们将通过检查对肠道生理和迷走感觉系统的影响来调节饱腹感。功能表征 Gpr17 信号传导并确定增强 GLP-1 分泌的分子机制我们的初步数据和体外和体内模型的可用性证明。支持我们提出的研究的可行性。成功完成该提案后，我们期望确定肠道中 Gpr17 信号传导对全身葡萄糖代谢和饱腹感的代谢影响这些研究将为识别脑肠中针对 Gpr17 的新型分子奠定基础。开发潜在治疗方法的轴。