Illuminating the Metabolic Function of GPR162 by Delineating Downstream Signaling Pathways and Characterizing Hypothalamic Expression Pattern

通过描绘下游信号通路和表征下丘脑表达模式来阐明 GPR162 的代谢功能

• 批准号: 10046905
• 负责人: Hongxia Ren
• 金额: $ 17.16万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046905
• 关键词: ARNT gene; Address; Affect; Agonist; Animal Model; Area; Arrestins; Behavior; Binding; Biological Assay; Biological Process; Biology; Brain; Brain region; CRISPR/Cas technology; Calories; Cardiovascular Diseases; Cell model; Cells; Chemicals; Chronic; Collaborations; Coupling; Critical Pathways; Cyclic AMP; Data; Development; Diabetes Mellitus; Drug Targeting; Drug or chemical Tissue Distribution; Eating; Endocrine; Environment; Family; Fluorescence; Food; Functional disorder; Funding; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genome; Goals; Grant; Health; Homeostasis; Hormones; Human; Human Genome; Hypothalamic structure; Incidence; Individual; Institutes; Investigation; Ion Channel; Ions; Joints; Knowledge; Label; Lead; Ligands; Light; Lipids; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolism; Methods; Modeling; Modernization; Molecular; Molecular Receptor Pharmacology; Morbidity - disease rate; Motivation; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Neurons; Neurosecretory Systems; Neurotransmitters; Obesity; Odors; Palate; Pattern; Peptides; Peripheral; Personal Communication; Pharmaceutical Preparations; Phosphotransferases; Photons; Physiological; Play; Prevalence; Property; Proteins; Public Domains; Publications; Reagent; Receptor Signaling; Regulation; Research; Research Personnel; Resources; Rewards; Role; Signal Pathway; Signal Transduction; Societies; Study models; Testing; Time; Tissues; Translating; Treatment Efficacy; United States; United States Food and Drug Administration; United States National Institutes of Health; Universities; Validation; Weight Gain; Work; base; brain cell; comorbidity; detection of nutrient; drug discovery; druggable target; energy balance; feeding; glucose metabolism; hedonic; mortality; neural circuit; novel; novel therapeutics; open source; overexpression; programs; protein expression; receptor; receptor function; recruit; repaired; response; screening; sedentary lifestyle; success; tool

PROJECT SUMMARY Of the twenty thousand proteins encoded in the human genome, three thousand of them are considered as part of the `druggable genome' by their estimated capability to bind drug-like molecules. Ion channels, kinases and G protein-coupled receptors (GCPRs) are three important components of the `druggable genome'. GPCRs are the most successful class of druggable targets. Currently, GPCRs are the target of over ~26% of the Food and Drug Administration (FDA) approved drugs. GPCRs are a family of seven-transmembrane (7TM) receptors that regulate important physiological functions through a diverse array of the endogenous ligands, which include light, odor, neurotransmitter, ion, hormone, peptide, lipid, metabolite, etc. Yet, despite of their functional importance and excellent druggability, a large number of non-olfactory GPCRs are still understudied, which is largely due to the unknown nature of the endogenous ligands and physiological functions. Therefore, there is an urgent need to characterize the understudies GPCRs by providing new research tools and characterize the physiological function of these receptors. Metabolic diseases, including diabetes and obesity, have become a major health problem worldwide. Sedentary lifestyles and the abundance of palatable and calorie-dense foods in modern societies have undoubtedly contributed to the increasing prevalence of obesity, which is associated with the incidence of multiple co-morbidities including diabetes and cardiovascular diseases. The brain is a key regulator for energy balance, owing to its ability to sense nutrients, control reward/motivation behavior, and orchestrate peripheral responses. The overarching goal of our research program is to understand the molecular mechanisms of neurohormonal pathways critical for feeding and glucose metabolism. Specifically, we aim to focus on the understudied GPCRs in the neuroendocrine system and study their roles in the pathophysiology of obesity and diabetes. Our preliminary study showed that GPR162 expression in the hypothalamus is regulated by feeding conditions and correlated with metabolic derangements. Our data, together with data from the public domain, strongly suggest that more investigations are needed to understand the upstream signals and downstream activities of this understudied GPCR and its relevance to metabolic disease pathophysiology. By characterizing the tissue / cell expression and the signaling properties of this GPCR, we will establish key background knowledge that is necessary to develop developing screening assays and performing pilot screening to obtain agonist and antagonist for GPR162. Moreover, the results from this work will have the potential to translate to humans and to the development of novel therapeutic reagents for metabolic diseases. This complementary expertise of the investigators in GPCR biology and metabolism and the on-going collaboration support the feasibility and increase the likelihood of success. Successful completion of this study will serve as preliminary data for the subsequent NIDDK R01 applications and/or drug discovery projects.

项目摘要 在人类基因组中编码的两万种蛋白质中，有三千种被认为是 “药物基因组”的估计能力结合药物样分子。离子通道、激酶和 G蛋白偶联受体是“可用药基因组”的三个重要组成部分。gpcr是 最成功的一类药物靶点目前，GPCR是超过26%的食品和饮料的目标， 美国药品管理局（FDA）批准的药物。GPCR是七跨膜（7 TM）受体家族， 通过多种内源性配体调节重要的生理功能，这些内源性配体包括光， 气味，神经递质，离子，激素，肽，脂质，代谢物等。然而，尽管它们的功能重要性 和优良的可药用性，大量的非嗅觉GPCR仍然研究不足，这主要是由于 内源性配体和生理功能的未知性质。因此，迫切需要 通过提供新的研究工具来表征待研究的GPCR， 这些受体的功能。代谢性疾病，包括糖尿病和肥胖，已成为一个主要的健康 全世界的问题。久坐不动的生活方式和现代社会丰富的可口和高热量的食物 毫无疑问，社会对肥胖症的日益流行做出了贡献，这与肥胖症有关。 多种合并症的发生率，包括糖尿病和心血管疾病。大脑是一个关键的调节器 对于能量平衡，由于其能够感知营养、控制奖励/激励行为并协调 周边反应我们研究计划的首要目标是了解 对进食和葡萄糖代谢至关重要的神经激素途径。具体而言，我们的目标是集中在 深入研究了神经内分泌系统中的GPCR，并研究了它们在肥胖症病理生理学中的作用， 糖尿病我们的初步研究表明，GPR 162在下丘脑中的表达受进食的调节， 条件和相关的代谢紊乱。我们的数据，以及来自公共领域的数据， 我强烈建议，需要更多的调查，以了解上游信号和下游 这种GPCR的活性及其与代谢疾病病理生理学的相关性未得到充分研究。通过表征 该GPCR的组织/细胞表达和信号传导特性，我们将建立关键背景 开发筛选试验和进行中试筛选以获得 GPR 162的激动剂和拮抗剂。此外，这项工作的结果将有可能转化为 本发明还涉及用于人类的新的治疗试剂的开发。这种互补 研究人员在GPCR生物学和代谢方面的专业知识以及正在进行的合作支持了 提高可行性，增加成功的可能性。成功完成这项研究将作为初步的 用于后续NIDDK R 01应用和/或药物发现项目的数据。