Ciliary trafficking mechanisms underlying the human genetics of obesity

人类肥胖遗传学的纤毛运输机制

基本信息

批准号：
9980198
负责人：
PETER Kent JACKSON
金额：
$ 48.92万
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 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980198
关键词：
Adenylate Cyclase Affect Affinity Chromatography Ankyrin Repeat Apical Architecture Bardet-Biedl Syndrome Binding Biochemical Biological Models Brain Calcium Calcium Signaling Carrier Proteins Cell Cycle Cells Cellular biology Centrioles Cilia Complex Cyclic AMP Defect Developed Countries Disease Distal Drug Modelings FREQ gene Family Feeding behaviors Froehlich&apos s Syndrome G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Genes Genetic Transcription Goals Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Health Care Costs Homologous Protein Human Human Genetics Hyperphagia Hypothalamic structure Kidney Diseases Knockout Mice Leptin Lesion Link Mass Spectrum Analysis Metabolic Metabolism Modeling Molecular Molecular Analysis Morbidity - disease rate Neuraxis Neurons Obesity Obesity Epidemic Pathway Analysis Pathway interactions Patients Peripheral Pilot Projects Positioning Attribute Proteins Proteomics Radial Regulation Retinal Degeneration Role Sensory Signal Pathway Signal Transduction Signaling Protein Site Structure Syndrome Testing Tissues Work appendage base ciliopathy drug discovery feeding gene product human disease human subject in vivo insight kinetosome link protein lipid biosynthesis mouse model neuropeptide Y novel obesity genetics patient population receptor recruit scaffold sensor trafficking

项目摘要

PROJECT SUMMARY Primary cilia are signaling centers directing sensory signaling in diverse tissues including the brain. Human ciliopathies including Bardet-Biedl syndrome present with a range of deficiencies including retinal degeneration, renal disease, and hyperphagia-driven hypothalamic obesity. Using tandem affinity purification of ciliopathy gene products, the lab has identified key regulators and effectors of these disease genes. Specifically, identification of the BBSome, a complex in central to Bardet-Biedl syndrome provided key insights into the trafficking of GPCRs into cilia. Extending the strategy to look systematically at proteins interacting with the gene products of monogenic obesity syndromes, the Tubby obesity protein was found copurifying with the intraflagellar A complex. Both BBS and Tubby/Tulp3 are important regulators of GPCR trafficking into primary cilia, providing important criteria to identify bona fide ciliary receptors. Using these criteria, the neuropeptide Y family of GPCRs, notably NPY2R, were discovered to be an important determinant of Bardet-Biedl syndrome. This proposal is focused on the newly identified monogenic obesity gene Cep19, which is recruited by FGFR1OP/FOP, CEP350 and a new ciliary GTPase and a candidate obesity gene, Rabl2B. Work here led to the discovery that the IFT-B complex is the central effector of Rabl2B and that Rabl2B is required for IFT-B to assemble cilia. By defining mechanisms regulating the Rabl2B GTPase mechanism, including the identification of GEF and GAP, a critical goal is to understand how the entry of IFT-B into cilia is regulated and how misregulation causes defects in ciliary trafficking of obesity regulators. Additional studies will focus on the ciliary anchors for the Cep19-Rabl2B pathway on the ciliary distal appendage, a set of two pilot studies to look at interactions from two other monogenic obesity genes, adenylate cyclase 3 and Ncs1, and finally to look these trafficking mechanisms controlling GPCR trafficking, the effects of these pathways in Rabl2 knockout mice, and to look for additional human patient lesions in newly identified candidate obesity genes.

项目摘要原发性纤毛是信号传导中心，指导包括大脑在内的各种组织中的感觉信号传导。人类纤毛病，包括带有一系列缺陷的Bardet-Biedl综合症，包括视网膜变性，肾脏疾病和噬菌体驱动的下丘脑肥胖。使用串联亲和力净化在纤毛病基因产物中，该实验室确定了这些疾病基因的关键调节剂和效应因子。具体而言，BBSOME的识别，Bardet-Biedl综合征中心的综合体提供了关键的见解进入GPCR贩运纤毛。扩展策略以系统地观察与之相互作用的蛋白质发现单基因肥胖综合征的基因产物，发现肥胖蛋白与 flagellar内综合体。 BBS和Tubby/Tulp3都是GPCR贩运的重要调节因子纤毛，提供重要的标准来识别真正的睫状受体。使用这些标准，神经肽y 发现GPCR家族，尤其是NPY2R，是Bardet-Biedl综合征的重要决定因素。该提案的重点是新确定的单基因肥胖基因CEP19，该基因是由 FGFR1OP/FOP，CEP350和新的睫状GTPase和候选肥胖基因，Rabl2b。在这里工作导致发现IFT-B复合物是Rabl2b的中心效应器，并且IFT-B需要RABL2B 组装纤毛。通过定义调节RABL2B GTPase机制的机制，包括识别GEF和GAP，一个关键目标是了解如何调节IFT-B进入纤毛的进入以及骨髓在肥胖调节剂的睫毛贩运中如何导致缺陷。其他研究将重点放在纤毛远端附属物上CEP19-RABL2B途径的睫状锚，这是一组两项试验研究在其他两个单基因肥胖基因的相互作用中，腺苷酸环化酶3和NCS1，最后是这些控制GPCR贩运的贩运机制，这些途径在Rabl2敲除中的影响小鼠，并在新鉴定的候选肥胖基因中寻找其他人类患者病变。