Understudied GPCRs connecting signaling in primary cilia to obesity and metabolic disease

这个项目的重点是了解控制摄食和呼吸的基本细胞机制 人类的肥胖。这种机制使用一种古老的细胞信号细胞器，即初级纤毛来控制 对喂食后产生的饱腹感信号的反应。Bardet-Biedl综合征是一种罕见的人类综合征 由于编码初级纤毛成分的基因突变，因此被称为纤毛病。患有疾病的患者 BBS基因的突变继承了与一种名为BBSome的复合体相关的基因突变，该复合体在 我们的实验室，未能提供对控制餐后进食至关重要的G蛋白偶联受体。一个 由Tubby/TULP3-IFT-A复合体组织的额外途径对于GPCRs和其他 信号分子进入纤毛。这些转运途径控制着调节进食和饱足的基本GPCR。 下丘脑和纤毛的缺陷会导致摄食控制的丧失。我们的研究发现纤毛也控制着 脂肪组织的产生和胰岛素通过胰腺的分泌，增加了对中枢神经系统的外周控制 监管。我们已经在纤毛疾病、单基因肥胖综合征和现在的GWAS研究中发现， 结构或信号成分，或受体本身可导致纤毛信号的严重缺陷。我们的 目前的假设是，纤毛基因的这些不同突变的总和构成了一些复杂性的基础， 肥胖和代谢性疾病的多基因特性。我们之前已经搜索过已知与 发现了许多定位于纤毛的受体，包括这里描述的三个新的受体GPR45、GPR63和 GPR135。这些受体与肥胖和代谢性疾病有特定的联系，包括小鼠的初步数据 和人类基因组广泛关联研究。找到一个或多个与新陈代谢有关的受体 疾病可能会为肥胖症或糖尿病的治疗提供新的理解和新的靶点。 创建这些第一个模型也将促进这些小鼠和其他导致肥胖的纤毛驱动因素的交叉 更好地了解肥胖和糖尿病的复杂多基因驱动因素。初步研究 因此，这里提出的建议将作为一座桥梁，通向后来专注于在 这里的这些筛查研究。具体目的为：目的1构建小鼠GPR45、GPR63和GPR63的KO GPR135和肥胖表型测试；Aim 2使用新产生的抗体来确定 Aim 3利用KO小鼠的组织蛋白质组学来了解GPCRs的分子表型。 发信号。通过识别肥胖和糖尿病中有缺陷的信号通路，我们可以识别保护或 恢复患者的这些组织和分子图谱，以方便患者的选择。

This project focuses on understanding a fundamental cellular mechanism underlying the control of feeding and obesity in humans. The mechanism uses an ancient cellular signaling organelle, the primary cilium, to control responses to satiety signals generated following feeding. Bardet-Biedl syndrome (BBS) is a rare human syndrome called a ciliopathy because of mutations in genes encoding components of the primary cilium. Patients with mutations in BBS genes have inherited mutations in genes linked to a complex called the BBSome, discovered in our laboratory, that fail to present G-protein coupled receptors critical to controlling feeding after a meal. An additional pathway organized by the Tubby/TULP3-IFT-A complex is essential for entry of GPCRs and other signaling molecules into cilia. These trafficking pathways control essential GPCRs that regulate feeding and satiety in the hypothalamus and defects in cilia cause a loss of feeding control. Our work has found that cilia also control the generation of fat tissue and the secretion of insulin via the pancreas, adding peripheral control to CNS regulation. We have found in ciliopathies, monogenic obesity syndromes and now GWAS studies that mutations in structural or signaling components, or in the receptors themselves can cause strong defects in ciliary signaling. Our current hypothesis is that the sum of these diverse mutations in ciliary genes underlie some of the complex, polygenic nature of obesity and metabolic disease. We have previously searched GPCRs known to be linked to metabolism and found many localized to cilia including three new receptors described here GPR45, GPR63 and GPR135. These receptors have specific links to obesity and metabolic disease including preliminary mouse data and human Genome Wide Associations Studies. Finding one or more these receptors linked to metabolic disease may offer new understanding and new targets for much needed therapeutics for obesity or diabetes. Creating these first models will also facilitate intercrossing of these mice and other ciliary drivers of obesity to build a better picture of the complex polygenic drivers of obesity and diabetes. The preliminary studies proposed here would thus serve as a bridge to later funding focused on the best candidates discovered in these screening studies here. The specific aims are: Aim 1 Construct mouse KOs of GPR45, GPR63 and GPR135 and test for obesity phenotypes; Aim 2 Use newly produced antibodies to determine the target tissues for these orphan GPCRs; and Aim 3 Use tissue proteomics of KO mice to understand the molecular phenotypes of signaling. By identifying signaling pathways defective in obesity and diabetes, we can identify targets to protect or restore these tissues and molecular profiles of patients to facilitate patient selection.