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性背后的基本细胞机制人类的生理信号，包括控制进食和肥胖，该机制使用了一种古老的机制。细胞信号细胞器，初级纤毛，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，称为纤毛病，因为编码基因发生突变 BBS 患者的初级纤毛成分遗传了与称为复合体的基因突变。我们实验室发现的 BBSome 无法呈现对限制餐后进食至关重要的受体。研究发现，纤毛还通过新脂肪细胞的从头生成和分泌我们关注胰岛细胞中的胰岛素和胰高血糖素的纤毛信号传导和运输机制。通过使用亲和纯化/质谱法来识别睫状机械的新组件。这些研究是通过使用纤毛病疾病基因作为诱饵蛋白来寻找新成分而开始的以及与纤毛交通和信号传导相关的细胞生物学途径。在与肥胖相关的人类谱系中，它们本身发生了突变，特别是称为远端的睫状结构。附属物是进入纤毛受体的关键门户，我们发现远端成分发生突变。由于单基因肥胖综合征很少见，因此实验室发现附件与单基因肥胖综合征有关。转向在全基因组关联研究中系统地调查超过 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，以及我们已经发现了数百个甚至数千个候选者，用于更广泛的糖尿病候选者名单。在该提案的目标 1 中，我们将进一步探讨与非近亲结婚人群中的纤毛有关的肥胖驱动因素。远端附肢的组装机制以及如何组织运输到纤毛。目标 2，我们将研究远端附肢如何在细胞中运输受体并产生信号。将探索远端附属物的一种新因子，称为 CCDC92，它可能通过蛋白水解控制信号传导在每个目标中，我们将使用来自高危患者的遗传性病变。我们发现 BMI 可以筛查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，以便准确评估患者的遗传性肥胖驱动因素，以确定其他可药物治疗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易感性通过识别肥胖和肥胖的信号通路缺陷。糖尿病，我们可以确定目标来保护或恢复患者的这些组织和分子谱，以促进患者选择改善肥胖和代谢疾病的治疗方法。