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.

这个项目的重点是了解一个基本的细胞机制的控制喂养和 肥胖症该机制使用一个古老的细胞信号细胞器，初级纤毛，控制 对进食后产生的饱足感信号的反应。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发生突变而被称为纤毛病。患者 BBS基因中的突变遗传了与一种称为BBSome的复合体相关的基因中的突变， 我们的实验室，未能提出G蛋白偶联受体控制进食后的关键。一个 由Tubby/TULP 3-IFT-A复合物组织的另外的途径对于GPCR和其他细胞因子的进入是必需的。 信号分子进入纤毛。这些运输途径控制着调节进食和饱腹感的基本GPCR 以及纤毛的缺陷导致进食控制的丧失。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CNS的外周控制 调控我们在纤毛病变、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，或受体本身中的结构或信号成分，可引起纤毛信号传导的强烈缺陷。我们 目前的假设是纤毛基因中这些不同突变的总和是某些复合物的基础， 肥胖和代谢性疾病的多基因性质。我们之前已经搜索了已知与 代谢，发现许多定位于纤毛，包括本文描述的三种新受体GPR 45，GPR 63和GPR 64。 GPR135。这些受体与肥胖和代谢疾病有着特定的联系，包括初步的小鼠数据。 和人类全基因组关联研究。找到一个或多个与代谢有关的受体 疾病可能为肥胖症或糖尿病的急需治疗提供新的认识和新的靶点。 创建这些第一个模型也将促进这些小鼠和其他肥胖的纤毛驱动因子的交叉， 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，这里提出的将作为一个桥梁，以后来的资金集中在最好的候选人发现， 这些筛选研究目的1构建GPR 45、GPR 63和GPR 64的小鼠科斯克隆， GPR 135和肥胖表型的测试;目的2使用新产生的抗体来确定肥胖表型的靶组织。 目的3利用基因敲除小鼠的组织蛋白质组学来了解基因敲除小鼠的分子表型。 发信号。通过识别肥胖症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谱以便于患者选择。