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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：
10798011
负责人：
PETER Kent JACKSON
金额：
$ 25万
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/10798011
关键词：
Adipocytes Affinity Chromatography Bardet-Biedl Syndrome Biological Cells Cilia Communication Complex Data Defect Diabetes Mellitus Disease Distal Generations Genes Genetic Glucagon Goals Human Inherited Islet Cell Islets of Langerhans Laboratories Lesion Link Mass Spectrum Analysis Measures Metabolic Diseases Molecular Genetics Molecular Profiling Mutate Mutation Obesity Organelles Pathway interactions Patient Selection Patients Physiological Population Predisposition Proteins Satiation Selection for Treatments Signal Pathway Signal Transduction Structure Surveys Syndrome Therapeutic Tissues Work appendage ciliopathy dietary druggable target feeding genetic pedigree genome wide association study high body mass index improved insulin secretion lipid biosynthesis mass spectrometer obesity genetics profiles in patients rare condition receptor response 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.

该项目的重点是了解一系列重要的细胞机制的基础生理信号，包括控制进食和肥胖。该机制使用一个古老的细胞信号细胞器，初级纤毛，以控制对进食后产生的饱足信号的反应。 Bardet-Biedl综合征（BBS）是一种罕见的人类综合征，称为纤毛病，因为编码初级纤毛的组成部分。BBS患者遗传了与一种称为在我们的实验室中发现的BBSome，未能呈现对限制餐后进食至关重要的受体。我们研究发现，纤毛还通过新脂肪细胞的重新产生和胰岛素和胰高血糖素。我们专注于纤毛信号传导和运输的机制，能够通过使用亲和纯化/质谱法来鉴定纤毛机构的新组分。这些研究已经开始使用纤毛疾病基因作为诱饵蛋白，以寻找新的成分以及与纤毛运输和信号传导相关的细胞生物学途径。一些新发现的成分在与肥胖有关的人类谱系中也发生了突变。特别是一种叫做远端的纤毛结构附件作为纤毛受体进入的关键门。我们发现，在远端的组件突变，与单基因肥胖综合征有关。由于单基因肥胖综合征很罕见，实验室转移到系统地调查全基因组关联研究中超过750，000名患者的公共数据（GWAS）发现在高体重指数（BMI）（肥胖的关键指标）患者中发生改变的基因，糖尿病我们已经发现了100多个候选人，如果不是1000多个候选人的话，非血缘人群中与纤毛相关的肥胖驱动因素。在本建议的目标1中，我们将进一步探讨远侧附肢的组装机制以及如何组织运输进入纤毛。在目的2，我们将研究远端附件如何在细胞中运输受体并产生信号。在目标3中，我们将探索一种新的远端附件因子，称为CCDC 92，它可能通过蛋白水解控制信号传导破坏纤毛信号调节器。在每个目标中，我们将使用来自高血压患者的遗传病变，我们发现BMI已经筛选出纤毛运输或信号传导的缺陷。我们的目标是继续解释肥胖病变，以允许准确评估患者的遗传肥胖驱动因素，肥胖和糖尿病治疗的目标，并将这些发现传达给公众以帮助预测饮食基于分子遗传图谱的亲和性。通过识别肥胖症中有缺陷的信号通路，糖尿病，我们可以确定目标，以保护或恢复这些组织和患者的分子概况，以促进选择患者进行治疗以改善肥胖和代谢疾病。