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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.

这个项目的重点是了解一个基本的细胞机制控制进食和