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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：
10899394
负责人：
Jeremy F Reiter
金额：
$ 7.97万
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/10899394
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 Cytoplasm 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 Persons 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 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.

项目摘要/摘要我们研究神经元初级纤毛如何调节能量动态平衡以及如何它们的失调会导致肥胖。初级纤毛是细胞表面的突起，它接收并转换精选的细胞间信号。在人类中，初级纤毛功能障碍导致纤毛病，肥胖是其主要表现的多发性疾病。这个人类严重肥胖最常见的单基因原因是MC4R基因突变，编码调节能量动态平衡的下丘脑GPCR。在这个项目的最初资助期，我们已经证明了MC4R 在体内的初级纤毛的定位和功能，以及它的定位和功能是依赖于MC4R相关蛋白MRAP2。我们还发现，抑制 MC4R神经元初级纤毛中的腺苷环化酶导致肥胖。这些发现提示下丘脑神经元利用纤毛通过MC4R进行通讯调节能量平衡。在这里，我们建立在这些发现和我们拥有的新的遗传和分子工具的基础上研究纤毛病变如何扰乱睫状体MC4R信号，如何通过配体调节其对纤毛的定位，以及MC4R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能量动态平衡和神经元如何使用纤毛进行非突触通信。