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

正在研究将初级纤毛信号与肥胖和代谢疾病联系起来的 GPCR

• 批准号: 10452377
• 负责人: PETER Kent JACKSON
• 金额: $ 15.99万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452377
• 关键词: Adipocytes; Affinity; Agonist; Antibodies; Automobile Driving; B-Lymphocytes; Bardet-Biedl Syndrome; Binding; Biology; Brain; Cells; Cilia; Clinical Research; Complex; DNA Sequence Alteration; Data; Databases; Defect; Diabetes Mellitus; Diabetic mouse; Disease; Embryo; Endocrine; Endocrine Glands; Fatty Acids; Fatty acid glycerol esters; Funding; G-Protein-Coupled Receptors; Galanin; Generations; Genes; Genetic; Genetic Transcription; Glucagon; Health; High Fat Diet; Human; Human Genetics; Human Genome; Hypothalamic structure; Inherited; Islets of Langerhans; Knock-out; Knockout Mice; Laboratories; Ligands; Link; Malignant Neoplasms; Membrane; Metabolic; Metabolic Diseases; Metabolism; Missense Mutation; Modeling; Molecular Profiling; Mus; Mutation; Nature; Neurons; Neuropeptide Y Receptor; Obese Mice; Obesity; Organelles; Orphan; Pancreas; Paper; Pathology; Pathway interactions; Patient Selection; Patients; Peripheral; Phenotype; Play; Proteomics; Publishing; Receptor Gene; Refractory; Regulation; Role; S phase; Satiation; Sensory; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Sum; Syndrome; Technology; Testing; Therapeutic; Tissues; Work; bile duct; ciliopathy; developmental disease; diagnostic signature; extracellular; feeding; genome wide association study; human tissue; insulin secretion; lipid biosynthesis; molecular phenotype; mouse genetics; mouse model; precision medicine; profiles in patients; programs; receptor; receptor expression; response; screening; tissue regeneration; trafficking

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.

该项目的重点是理解喂养控制和控制的基本细胞机制 人类肥胖。该机制使用古老的细胞信号传导细胞器（主要纤毛）来控制 喂食后产生的对饱腹感信号的响应。 Bardet-Biedl综合征（BBS）是一种罕见的人类综合征 由于编码原发性纤毛成分的基因突变而称为纤毛病。患者 BBS基因中的突变在与一个称为BBSOME的复合物相关的基因中遗传了突变， 我们的实验室无法呈现G蛋白偶联受体，这对于在饭后控制喂养至关重要。一个 Tubby/Tulp3-Ift-A复合物组织的其他途径对于进入GPCR和其他 信号分子到纤毛中。这些贩运途径控制着调节喂养和饱腹感的必需GPCR 在下丘脑和纤毛中的缺陷中，导致喂养控制丧失。我们的工作发现西里亚也控制了 脂肪组织的产生和通过胰腺分泌胰岛素的分泌，为CNS增加外围控制 规定。我们在纤毛病，单基因肥胖综合征和GWAS研究中发现了突变 结构或信号传导成分或受体本身可能会在睫状信号传导中引起强缺陷。我们的 当前的假设是，这些睫状基因中这些多种突变的总和是其中一些复合物， 肥胖和代谢疾病的多基因性质。我们以前已经搜索已知已链接到的GPCR 代谢，发现许多与纤毛的本地化，包括此处描述的三个新受体，GPR45，GPR63和 GPR135。这些受体与肥胖和代谢疾病（包括初步小鼠数据）有特定的联系 和人类基因组广泛的关联研究。找到一个或多个与代谢相关的受体 疾病可能为肥胖或糖尿病急需的治疗剂提供新的理解和新目标。 创建这些最初的模型还将促进这些小鼠和其他肥胖的睫毛驱动器的跨性交 更好地了解肥胖和糖尿病的复杂多基因驱动器。初步研究 因此，这里提出的建议将作为后来的资金的桥梁，专注于发现的最佳候选人 这些筛查研究。具体目的是：AIM 1构造GPR45，GPR63和 GPR135和测试肥胖表型； AIM 2使用新生产的抗体来确定目标组织 这些孤儿GPCR；目标3使用KO小鼠的组织蛋白质组学来了解 信号。通过确定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特征，以促进患者选择。