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

项目总结 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 根据估计的与类药物分子结合的能力来确定“可药物基因组”的数量。离子通道、激酶和 G蛋白偶联受体(GCPRs)是“可药物基因组”的三个重要组成部分。GPCR是 最成功的一类可下药靶子。目前，GPCRs是超过26%的粮食和 美国药品监督管理局(FDA)批准的药物。GPCRs是一个七跨膜(7TM)受体家族， 通过一系列不同的内源性配体调节重要的生理功能，其中包括光， 气味、神经递质、离子、激素、肽、脂类、代谢物等，尽管它们在功能上很重要 和良好的药效性，但大量的非嗅觉GPCR仍未得到充分研究，这在很大程度上是由于 内源性配体的性质和生理功能尚不清楚。因此，迫切需要 通过提供新的研究工具来表征候补GPCRs和表征生理学 这些受体的功能。代谢性疾病，包括糖尿病和肥胖症，已经成为一种主要的健康 这是世界性的问题。现代久坐不动的生活方式和丰富的美味和高热量食物 社会无疑是导致肥胖症日益流行的原因之一，肥胖与 多种并存疾病的发生率，包括糖尿病和心血管疾病。大脑是一个关键的调节器 能量平衡，因为它有能力感知营养，控制奖励/激励行为，并协调 外周反应。我们研究计划的首要目标是了解分子机制。 对进食和葡萄糖代谢至关重要的神经激素途径。具体地说，我们的目标是专注于 未充分研究GPCRs在神经内分泌系统中的作用，并研究它们在肥胖和 糖尿病。我们的初步研究表明，GPR162在下丘脑的表达受摄食的调节 并与代谢紊乱相关。我们的数据，连同来自公共领域的数据， 强烈建议需要更多的研究来了解上游和下游的信号 这一未被研究的GPCR活性及其与代谢性疾病病理生理学的相关性。通过刻画 组织/细胞表达和信号转导特性，我们将建立关键背景 开发开发筛查分析和进行试点筛查以获得 GPR162的激动剂和拮抗剂。此外，这项工作的结果将有可能转化为 对人类和新陈代谢疾病治疗试剂的开发做出了贡献。这种互补性 研究人员在GPCR生物学和新陈代谢方面的专门知识以及正在进行的合作支持 可行性和增加成功的可能性。成功完成这项研究将作为初步工作 为后续的NIDDK R01应用和/或药物发现项目提供数据。

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.