The Role of cAMP Signaling in Neuronal Primary Cilia

cAMP 信号传导在神经元初级纤毛中的作用

基本信息

批准号：
9211722
负责人：
Xuanmao Chen
金额：
$ 20.96万
依托单位：
UNIVERSITY OF NEW HAMPSHIRE
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：
2017-08-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9211722
关键词：
Ablation Adenylate Cyclase Anosmia Area Biomedical Engineering Brain Carrier Proteins Cilia Cognitive deficits Cyclic AMP Cyclic AMP-Dependent Protein Kinases Defect Disease Enzymes Future Gene Expression Generations Genes Genetic Genetic Engineering Genetic study Goals Golf Hormones Human Human Genetics Hypothalamic structure Impairment Infertility Intervention Knockout Mice Label Light LoxP-flanked allele Major Depressive Disorder Mass Spectrum Analysis Mediating Mental Depression Methods Molecular Mood Disorders Mus Neuraxis Neurons Obesity Odors Organelles Pathway interactions Phenotype Physiological Polymers Proteins Proteomics Research Rodent Role Sensory Serotonin Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Protein Sleep Smell Perception System Testing Tissues adenylyl cyclase III base ciliopathy cyclic-nucleotide gated ion channels desensitization energy balance experimental study extracellular human disease improved insight nanoparticle novel olfactory sensory neurons optogenetics protein transport receptor therapy design tool

项目摘要

PROJECT SUMMARY (CHEN, JI) Primary cilia are the “cellular antennae” that detect various extracellular signals including hormones. Defects in primary cilia cause a broad spectrum of human diseases including obesity. The type 3 adenylyl cyclase (AC3) is the major adenylyl cyclase and a key enzyme mediating the cAMP signal pathway in olfactory sensory cilia and in primary cilia throughout the central nervous system (CNS). AC3 in olfactory sensory cilia is essential for the olfactory signal transduction and loss of AC3 leads to anosmia (loss of smell). Moreover, multiple genetic evidence has demonstrated that defects in AC3 are associated with obesity and depression. Nevertheless, the functional mechanisms of AC3, and the signaling transduction pathway in primary cilia in the CNS remain to be elucidated. Because olfactory sensory cilia and neuronal primary cilia are structurally related and share a common intraflagellar protein transport system, we hypothesize that the cAMP signaling in the primary cilia of CNS neurons resembles that in olfactory sensory cilia and alteration of this signaling in neuronal primary cilia impacts obesity and depression. To test this hypothesis, we will first use fluorescent nanoparticles in co- immnunostaining experiments and take a mass spectrometry based proteomic approach to identify signal proteins that transduce the cAMP signaling in the primary cilia of CNS neurons. We will next genetically engineer a light-activated adenylyl cyclase into primary cilia to enable optogenetic manipulation of cAMP level in neuronal primary cilia. We will also determine how cAMP in neuronal primary cilia modulate neuronal functions. In addition, we will further identify which neuronal ensembles with loss of AC3 leads to obesity and depression using tissue-specific AC3 knockout mice. Completion of this project will identify molecular components that mediate ciliary cAMP signal transduction, generate useful tools for cilium research, and provide novel insights into the (patho-)physiological roles of AC3 in obesity and depression.

项目概要（陈、吉）初级纤毛是“细胞天线”，可以检测各种细胞外信号，包括激素缺陷。初级纤毛会导致包括肥胖在内的多种人类疾病。是主要的腺苷酸环化酶，也是嗅觉纤毛中介导 cAMP 信号通路的关键酶在整个中枢神经系统 (CNS) 的初级纤毛中，AC3 对嗅觉感觉纤毛至关重要。嗅觉信号转导和 AC3 缺失会导致嗅觉丧失（嗅觉丧失）。有证据表明 AC3 缺陷与肥胖和抑郁症有关。 AC3的功能机制以及中枢神经系统初级纤毛的信号转导途径仍有待进一步研究因为嗅觉纤毛和神经元初级纤毛在结构上相关并且共享一个。常见的鞭毛内蛋白质转运系统，我们假设初级纤毛中的 cAMP 信号传导中枢神经系统神经元与嗅觉感觉纤毛中的神经元类似，并且神经元初级纤毛中信号传导的改变为了验证这一假设，我们将首先使用荧光纳米粒子来共同研究。免疫染色实验并采用基于质谱的蛋白质组学方法来识别信号接下来我们将从基因角度研究在 CNS 神经元初级纤毛中转导 cAMP 信号传导的蛋白质。将光激活的腺苷酸环化酶工程化到初级纤毛中，以实现 cAMP 水平的光遗传学操作我们还将确定神经元初级纤毛中的 cAMP 如何调节神经元此外，我们将进一步确定哪些神经元缺失 AC3 会导致肥胖和肥胖。使用组织特异性 AC3 敲除小鼠进行抑郁症的研究完成该项目将鉴定分子。介导 cAMP 信号转导的成分，为纤毛研究生成有用的工具，以及为 AC3 在肥胖和抑郁症中的（病理）生理作用提供了新的见解。