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

基本信息

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
项目类别：
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

项目摘要

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.

该项目的重点是了解控制进食和进食的基本细胞机制。人类肥胖。该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进食后产生的饱腹感信号的反应。 Bardet-Biedl 综合征 (BBS) 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，称为纤毛病。患者患有 BBS 基因的突变继承了与 BBSome 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 Tubby/TULP3-IFT-A 复合体组织的额外途径对于 GPCR 和其他物质的进入至关重要信号分子进入纤毛。这些贩运途径控制着调节进食和饱腹感的重要 GPCR 下丘脑的缺陷和纤毛的缺陷会导致进食控制的丧失。我们的工作发现纤毛也控制通过胰腺产生脂肪组织和分泌胰岛素，增加中枢神经系统的外周控制规定。我们在纤毛病、单基因肥胖综合征以及现在的 GWAS 研究中发现，结构或信号成分，或受体本身可能导致纤毛信号传导的严重缺陷。我们的目前的假设是，睫状体基因中这些不同突变的总和构成了一些复杂的基础，肥胖和代谢疾病的多基因性质。我们之前搜索过已知关联的 GPCR 代谢，发现许多局限于纤毛，包括此处描述的三种新受体 GPR45、GPR63 和探地雷达135。这些受体与肥胖和代谢疾病有特定的联系，包括初步的小鼠数据和人类全基因组关联研究。寻找与代谢相关的一种或多种受体疾病可能为急需的肥胖或糖尿病治疗方法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，这里提出的建议将成为以后资助的桥梁，重点关注在中发现的最佳候选人这些筛选研究在这里。具体目标是：目标 1 构建 GPR45、GPR63 和 GPR45 的小鼠 KO GPR135 和肥胖表型测试；目标 2 使用新产生的抗体来确定靶组织这些孤儿 GPCR；目标 3 使用 KO 小鼠的组织蛋白质组学来了解发信号。通过识别肥胖和糖尿病中存在缺陷的信号通路，我们可以确定要保护或恢复患者的这些组织和分子特征，以方便患者选择。