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Mechanisms of Ciliary Signaling Controlling Obesity and Metabolic Disease

纤毛信号控制肥胖和代谢疾病的机制

基本信息

批准号：
10446951
负责人：
PETER Kent JACKSON
金额：
$ 50.62万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10446951
关键词：
26S proteasome Adipocytes Affect Affinity Chromatography Automobile Driving Bardet-Biedl Syndrome Binding Binding Proteins Biological Cell Culture Techniques Cells Cellular biology Centrioles Centrosome Cilia Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats Complex Coupling Data Defect Diabetes Mellitus Diagnosis Disease Distal Docking Embryo Endocrine Endosomes Excision FREQ gene Feedback G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Generations Genes Genetic Genetic Transcription Glucagon Goals Health Hormone Receptor Hormones Human Human Genetics Inherited Islet Cell Islets of Langerhans Knockout Mice Laboratories Lesion Ligands Link Malignant Neoplasms Manuscripts Mass Spectrum Analysis Measures Mediating Membrane Metabolic Diseases Microtubules Modeling Molecular Molecular Genetics Molecular Profiling Mothers Mutate Mutation Obesity Organelles Pancreatic Polypeptide Pathogenesis Pathology Pathway interactions Patient Selection Patients Phenotype Physiological Play Population Predisposition Preparation Process Proteins Proteomics Receptor Signaling Recycling Regulation Role Satiation Selection for Treatments Sensory Signal Pathway Signal Transduction Site Situs Inversus Structure Surveys Syndrome Technology Testing Therapeutic Tissues Vesicle Work appendage base ciliopathy developmental disease dietary druggable target extracellular feeding genetic pedigree genome wide association study high body mass index improved insulin secretion lipid biosynthesis multicatalytic endopeptidase complex myristoylation novel obesity genetics phosphoproteomics profiles in patients protein degradation protein function rare condition receptor recruit response scaffold screening tau-protein kinase tau-tubulin kinase tissue regeneration trafficking

项目摘要

This project focuses on understanding a fundamental cellular mechanism underlying a range of important physiological signaling in humans including the control of feeding and obesity. 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 BBS have inherited mutations in genes linked to a complex called the BBSome, discovered in our laboratory, that fail to present receptors critical to limit feeding after a meal. Our work has found that cilia also control adipogenesis via the de novo generation of new fat cells and the secretion of insulin and glucagon in pancreatic islet cells. We have focused on mechanisms of ciliary signaling and trafficking, enabled by the use of affinity purification/mass spectrometry to identify new components of the ciliary machinery. These studies have been initiated by using the ciliopathy disease genes as bait proteins to find new components and cell biological pathways linked to ciliary traffic and signaling. A number of these newly discovered components are themselves mutated in human pedigrees linked to obesity. In particular, a ciliary structure called the distal appendage serves as a critical gate for entry of ciliary receptors. We find that mutations in components of the distal appendage are linked to monogenic obesity syndromes. As monogenic obesity syndromes are rare, the lab has shifted to systematically surveying public data for over 750,000 patients in Genome Wide Association Studies (GWAS) for genes found to be altered in patients with high Body Mass Index (BMI) (a key measure of obesity) and diabetes. We have discovered 100s if not 1000s of candidates for a substantially broader list of candidates for obesity drivers linked to cilia in nonconsanguineous populations. In Aim 1 of this proposal, we will further explore the mechanisms by which the distal appendage is assembled and how that organizes trafficking into the cilium. In Aim 2, we will examine how the distal appendage traffics receptors and generates signals in the cell. In Aim 3, we will explore a new factor of the distal appendage, called CCDC92, which potentially controls signaling via proteolytic destruction of ciliary signaling regulators. In each Aim, we will use genetic lesions derived from patients with high BMI which we find have screened for defects in ciliary trafficking or signaling. Our goals are to continue to explain obesity lesions to allow accurate assessment of a patient’s genetic obesity drivers, to identify additional druggable targets for obesity and diabetes therapeutics, and to communicate these findings to the public to help predict dietary susceptibilities based on molecular genetic profiles. 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 for treatments to improve obesity and metabolic disease.

这个项目的重点是了解一个基本的细胞机制，其背后的一系列重要