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.

抽象的星形胶质细胞是人脑中最丰富的神经胶质细胞。星形胶质细胞与突触通过薄的相互作用直发星形胶质细胞过程对于适当的突触连通性和功能至关重要。每个鼠标星形胶质细胞发送一系列流程，估计会接触超过100,000个突触。数量星形胶质细胞及其与突触的相互作用的程度在整个演变过程中都增加了，表明星形胶质细胞与认知之间的紧密联系。此外，新兴的证据表明星形胶质细胞间隔相互作用会导致多种脑部疾病。与神经元突触相反然而，结构在很大程度上对星形胶质细胞的分子组成和机制视而不见核突触结构。此外，目前对如何破坏突变的了解很少星形胶质细胞间隔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，不可能纯化和鉴定富含亚细胞区域的蛋白星形胶质细胞。在这个项目中，我们将开发和利用创新的蛋白质组学和基因组编辑方法解决这些问题，揭示与和与之相关的星形胶质细胞过程的蛋白质和内部工作调制突触。我们预计这些数据将为未来提供一个新的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。