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Obesity in ciliopathies: How neuronal primary cilia control appetite

纤毛病中的肥胖：神经元初级纤毛如何控制食欲

基本信息

批准号：
10392041
负责人：
Jeremy F Reiter
金额：
$ 69.14万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10392041
关键词：
Address Adenylate Cyclase Affect Brain CRISPR interference CRISPR/Cas technology Calories Cell Surface Extensions Cells Cilia Communication Coupled Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Defect Desire for food Disease Funding G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Gene Expression Genes Genetic Heart Diseases Homeostasis Human Hyperphagia Hypothalamic structure Inherited Laboratories Leptin Ligands Malignant Neoplasms Melanocortin 4 Receptor Melanocortin 4 receptor mutation Molecular Mus Mutation Neuronal Dysfunction Neurons Obesity Pathway interactions Positioning Attribute Proteins Public Health Receptor Signaling Regulation Research Personnel Role Second Messenger Systems Signal Transduction Surface Susceptibility Gene Synapses Testing Work alpha-Melanocyte stimulating hormone base ciliopathy diabetes risk experimental study genetic approach genetic variant in vivo insight intercellular communication mouse model novel optogenetics paraventricular nucleus receptor receptor function targeted delivery tool trafficking

项目摘要

Project Summary/Abstract We investigate how neuronal primary cilia regulate energy homeostasis and how their dysregulation causes obesity. Primary cilia are cell surface projections that receive and transduce select intercellular signals. In humans, disruption of primary cilia function causes ciliopathies, pleiotropic diseases of which obesity is a cardinal manifestation. The most common monogenic cause of severe human obesity is mutation of MC4R, encoding a hypothalamic GPCR that regulates energy homeostasis. In the initial funding period of this project, we have demonstrated that MC4R localizes and functions at the primary cilia in vivo, and that its localization and function are dependent on the MC4R-associated protein MRAP2. We also found that inhibiting adenylyl cyclase in the primary cilia of MC4R neurons causes obesity. These findings suggest that hypothalamic neurons use cilia to communicate through MC4R to regulate energy homeostasis. Here, we build on these findings, and on new genetic and molecular tools we have developed, to investigate how ciliopathies disrupt ciliary MC4R signaling, how the ligands of MC4R regulate its localization to cilia, and how MC4R activity is transduced by the cilium. Together, these experiments will illuminate how cilia signaling encodes long-term energy homeostasis and how neurons use cilia to communicate non-synaptically.

项目总结/摘要我们研究了神经元初级纤毛如何调节能量稳态，它们的调节失调会导致肥胖。初级纤毛是细胞表面的突起，和选择性细胞间信号。在人类中，初级纤毛功能的破坏引起纤毛病变，这是一种多效性疾病，肥胖是其主要表现。的人类严重肥胖症最常见的单基因原因是MC 4 R突变，一种调节能量平衡的下丘脑GPCR 在该项目的初始资助期间，我们已经证明MC 4 R 在体内的初级纤毛中定位和起作用，并且其定位和功能是依赖于MC 4 R相关蛋白MRAP 2。我们还发现， MC 4 R神经元的初级纤毛中的腺苷酸环化酶引起肥胖。这些发现表明下丘脑神经元通过纤毛与MC 4 R进行通讯，能量平衡在这里，我们建立在这些发现的基础上，以及我们拥有的新的遗传和分子工具上，开发，调查如何纤毛病变破坏睫状MC 4 R信号，如何配体 MC 4 R调节其纤毛定位，以及MC 4 R活性是如何通过纤毛总之，这些实验将阐明纤毛信号如何编码长期的能量稳态和神经元如何使用纤毛进行非突触交流。