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：
10659121
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/10659121
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 Communication 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 Hormone secretion 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 Phosphotransferases Physiological Play Population Predisposition Preparation Process Proteins Proteomics 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.

该项目侧重于理解一系列重要的基本蜂窝机制人类的生理信号传导，包括控制和肥胖。该机制使用了古老的细胞信号传导细胞器（主要的纤毛）控制进食后产生的对饱腹感信号的反应。 Bardet-Biedl综合征（BBS）是一种罕见的人类综合征，称为纤毛病，因为编码基因突变主要纤毛的成分。 BBS患者具有与称为复合物有关的基因中的遗传突变在我们的实验室中发现的BBSOME未能提出对饭后限制进食至关重要的接收器。我们的工作发现，纤毛还通过从头产生新的脂肪细胞和分泌来控制脂肪形成胰岛细胞中的胰岛素和谷歌。我们专注于睫状信号和贩运的机制，通过使用亲和力纯化/质谱来识别睫状机械的新组件启用。这些研究是通过使用纤毛性疾病疾病基因作为诱饵蛋白来找到新成分的研究开始的和与睫状流量和信号传导相关的细胞生物学途径。这些新发现的组件中的许多他们本身以与肥胖有关的人类血统突变。特别是，一种称为不同的睫状结构附录是进入睫状受体的关键门。我们发现不同的组成部分中的突变附录与单基因肥胖综合症有关。由于单基因肥胖综合症很少见，因此实验室具有在基因组广泛的关联研究中，系统地调查了750,000多名患者的公共数据（GWAS）发现高体重指数（BMI）患者（肥胖症的关键量度）和糖尿病。我们发现了100秒，如果不是1000名候选人，以提供更广泛的候选人名单肥胖驱动因素与非习惯种群中的纤毛相关。在本提案的目标1中，我们将进一步探索远端附属组装的机制以及如何组织贩运纤毛的机制。 AIM 2，我们将检查远端附属流量接收器如何在单元格中生成信号。在AIM 3中，我们将探索远端附属物的新因素，称为CCDC92，该因素可能通过蛋白水解控制信号睫状信号调节器的破坏。在每个目标中，我们都将使用来自高的患者得出的遗传病变我们发现的BMI筛选了纤毛贩运或信号传导中的缺陷。我们的目标是继续解释肥胖病变以允许对患者的遗传肥胖驱动因素进行准确评估，以识别其他可药物肥胖和糖尿病治疗剂的靶标，并向公众传达这些发现以帮助预测饮食基于分子遗传谱的敏感性。通过识别肥胖症中有缺陷的信号通路和糖尿病，我们可以识别靶标，以保护或恢复患者的这些组织和分子特征以促进患者选择治疗以改善肥胖症和代谢疾病。