Role of Soluble Adenylate Cyclase in Reactive Astrocytes

可溶性腺苷酸环化酶在反应性星形胶质细胞中的作用

基本信息

批准号：
9134927
负责人：
Evan G Cameron
金额：
$ 5.24万
依托单位：
STANFORD UNIVERSITY
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：
2016-01-31 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9134927
关键词：
Address Adenylate Cyclase Adult Alleles Architecture Astrocytes Axon Biological Assay CNS degeneration Cell Death Cell Survival Coupling Crush Injury Cyclic AMP Data Degenerative Disorder Development Event Eye Failure Family Gene Expression Genes Glial Fibrillary Acidic Protein Gliosis Goals Homeostasis Hypertrophy Immunofluorescence Immunologic In Vitro Inflammation Injury Knock-out Lead Link Mammals Measures Mediating Metabolic Metabolic Pathway Metabolism Molecular Morbidity - disease rate Morphology Mus Natural regeneration Nerve Crush Nerve Regeneration Nervous System Physiology Neuraxis Neurites Neurodegenerative Disorders Neuroglia Neurons Optic Nerve Optic Nerve Injuries Pattern Physiology Play Process Reporting Retina Retinal Retinal Ganglion Cells Role Signal Transduction Site Source Synapses Testing Therapeutic Time Tissues Up-Regulation assay development astrogliosis axon growth axon regeneration base calcium bicarbonate cell type central nervous system injury in vivo in vivo regeneration knock-down migration myelination neuron development neuronal survival neuropathology novel therapeutics overexpression public health relevance research study response response to injury therapeutic target treatment strategy wound

项目摘要

DESCRIPTION (provided by applicant): Central nervous system (CNS) injury and/or degeneration triggers numerous changes in gene expression, signaling and cellular interactions that result in permanent changes in tissue architecture and CNS function. Astrocytes respond to injury in a process referred to as reactive astrogliosis that includes both beneficial and ultimatey harmful functions. Cyclic-AMP (cAMP) has been demonstrated to play a significant role in regulating astrocyte physiology both during development and in response to injury. Recently, soluble adenylyl cyclase (sAC), a unique bicarbonate- and calcium-activated source of cAMP, was shown to play a role in retinal ganglion cell (RGC) survival and axon growth. In astrocytes, sAC-mediated signaling underlies a major metabolic pathway that provides energy to neurons during ischemic-like conditions. Our and others' data suggest that sAC signaling in astrocytes is necessary for retinal ganglion cell (RGC) survival and perhaps for regeneration after optic nerve injury. Based on our preliminary data, I hypothesize that astrocyte sAC is required for RGC survival and neurite patterning during development, and that sAC activity in astrocytes promotes RGCs survival and regeneration after optic nerve injury. To address this hypothesis, I will determine the levels of sAC expression in astrocytes during development and after ONC injury by immunofluorescence. To investigate astrocyte sAC in retinal development and reactive astrogliosis, I will use a floxed sAC allele to conditionally knock-out sAC in astrocytes at differnt developmental time points and after optic nerve injury to specifically measure the effect of astrocyte sAC on RGCs. The overall goal of this study is to better understand how astrocyte sAC influences reactive astrogliosis and neuronal survival and regeneration, highlighting it as a potential therapeutic target.

描述（由申请人提供）：中枢神经系统（CNS）损伤和/或变性引发基因表达、信号传导和细胞相互作用的大量变化，从而导致组织结构和中枢神经系统功能的永久性变化，该过程称为损伤响应。反应性星形胶质细胞增生包括有益的和最终有害的功能，已被证明在星形胶质细胞发育过程和损伤反应中的生理学调节中发挥着重要作用。腺苷酸环化酶 (sAC) 是一种独特的碳酸氢盐和钙激活的 cAMP 来源，已被证明在星形胶质细胞中的视网膜神经节细胞 (RGC) 存活和轴突生长中发挥作用，sAC 介导的信号传导是提供主要代谢途径的基础。我们和其他人的数据表明，星形胶质细胞中的 sAC 信号传导对于视网膜神经节细胞 (RGC) 的存活乃至再生是必需的。根据我们的初步数据，我认为星形胶质细胞 sAC 是发育过程中 RGC 存活和神经突模式所必需的，并且星形胶质细胞中的 sAC 活性可促进视神经损伤后 RGC 的存活和再生。通过免疫荧光测定发育过程中和 ONC 损伤后星形胶质细胞中 sAC 的表达水平为了研究视网膜发育和反应性星形胶质细胞增生中的星形胶质细胞 sAC，我将使用floxed sAC 等位基因在不同发育时间点和视神经损伤后条件性敲除星形胶质细胞中的 sAC，以特异性测量星形胶质细胞 sAC 对 RGC 的影响本研究的总体目标是更好地了解星形胶质细胞 sAC 如何影响反应性星形胶质细胞增生和神经元。存活和再生，突出其作为潜在的治疗靶点。