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New Proteomic and Genome Engineering Approaches to Decipher Astrocyte Function at Synapses

破译星形胶质细胞突触功能的新蛋白质组学和基因组工程方法

基本信息

批准号：
9789247
负责人：
Cagla Eroglu
金额：
$ 70.53万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789247
关键词：
Affect Age Astrocytes Biochemical Brain Brain Diseases Brain region C-terminal CRISPR/Cas technology Cell Adhesion Molecules Cell surface Chimeric Proteins Cognition Complement Complex Data Development Disease Disease model Evolution Functional disorder Future Gene Expression Genome engineering Goals Homeostasis Human Impairment Individual Knock-out Knowledge Label Lead Link Mass Spectrum Analysis Mediating Membrane Methods Molecular Molecular Profiling Monitor Mus Mutation N-terminal Nervous System Physiology Neuroglia Neurons Neurosciences Pathology Pathway interactions Problem Solving Process Property Proteins Proteome Proteomics Reaction Regulation Resources Role Science Specific qualifier value Structure Surface Synapses Synaptic Transmission Synaptosomes Techniques Testing Thinness Touch sensation Viral Work base blind brain cell cell type extracellular genome editing in vivo innovation insight mouse model nervous system disorder neuroregulation novel postsynaptic protein complex reconstitution synaptic function synaptogenesis tool

项目摘要

ABSTRACT Astrocytes are the most abundant glial cells in the human brain. Interactions of astrocytes with synapses via thin perisynaptic astrocytic processes are critical for proper synaptic connectivity and function. Each mouse astrocyte sends out an extensive array of processes that are estimated to contact over 100,000 synapses. The number of astrocytes and the extent of their interactions with synapses have increased throughout evolution, indicating a close link between astrocytes and cognition. Moreover, emerging evidence suggests that dysfunction of astrocyte-synapse interactions contributes to a variety of brain disorders. In contrast to neuronal synaptic structures, however, we are largely blind to the molecular composition and mechanisms of the astrocytic perisynaptic structures. Moreover, there is currently very little understanding of how mutations that disrupt astrocyte-synapse interactions lead to synaptic pathologies. This is in large part because, unlike neuronal synaptic structures, it has not been possible to purify and identify proteins enriched at subcellular regions of astrocytes. In this project, we will develop and utilize innovative proteomic and genome editing approaches to solve these problems, revealing the proteins and inner workings of astrocyte processes that associate with and modulate synapses. We anticipate these data will provide a new and unparalleled molecular framework for future studies on astrocyte- neuron interactions.

摘要星形胶质细胞是人脑中含量最丰富的神经胶质细胞。星形胶质细胞与突触的相互作用突触周围的星形细胞突起对于正常的突触连接和功能至关重要。每只小鼠星形胶质细胞发出一系列广泛的过程，估计联系超过100,000个突触。数量星形胶质细胞及其与突触相互作用的程度在整个进化过程中都有所增加，这表明星形胶质细胞与认知之间的密切联系。此外，新出现的证据表明，大脑的功能障碍星形胶质细胞-突触的相互作用导致了多种脑部疾病。与神经元突触形成对比然而，我们很大程度上对星形细胞的分子组成和机制视而不见。突触周围结构。此外，目前对突变是如何破坏的了解很少。星形胶质细胞-突触的相互作用导致突触病理。这在很大程度上是因为，与神经元不同突触结构，目前还不可能提纯和鉴定富含在突触亚细胞区域的蛋白质。星形胶质细胞。在这个项目中，我们将开发和利用创新的蛋白质组和基因组编辑方法来解决这些问题，揭示与星形胶质细胞突起相关的蛋白质和内部工作机制调节突触。我们预计这些数据将为未来提供一个新的和无与伦比的分子框架星形胶质细胞-神经元相互作用的研究。