GIT1 Regulates Spine Morphogenesis and Synapse Formation

GIT1 调节脊柱形态发生和突触形成

基本信息

批准号：
7751888
负责人：
DONNA J WEBB
金额：
$ 28.51万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-25 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7751888
关键词：
Actins Adaptor Signaling Protein Adhesions Affect Binding Biological Biological Assay Biosensor Cells Complex Dendritic Spines Environment Family Family member Fibroblasts Fluorescence Resonance Energy Transfer GIT1 gene GTPase-Activating Proteins Genes Glutamate Receptor Goals Guanine Nucleotide Exchange Factors Hippocampus (Brain)Integrin Signaling Pathway Integrins Learning Libraries Memory Mental Retardation Mitogen-Activated Protein Kinases Modeling Molecular Monomeric GTP-Binding Proteins Morphogenesis Morphology Mutate Neurons PTK2 gene Pathway interactions Patients Preparation Process Regulation Research Personnel Role Shapes Signal Pathway Signal Transduction Site Slice Synapses Synaptic plasticity Testing Vertebral column Work base cognitive function in vivo member mutant novel p21 activated kinase postsynaptic presynaptic programs response rho rho GTP-Binding Proteins scaffold synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): Synapse formation and plasticity underlie normal cognitive functions, such as learning and memory. Previous studies point to a critical role for the regulation of actin dynamics and adhesion in synapse formation and plasticity. These processes can be brought together by GIT1, a recently characterized molecule that resides in pre and postsynaptic terminals of hippocampal neurons. GIT1 serves as an adapter that binds Rac effectors and regulators and other synaptic molecules. Our preliminary work has led to working hypotheses and the objective of this proposal is to rigorously test these hypotheses as outlined in the specific aims using cultures of dissociated hippocampal neurons and slice preparations. Specific Aim I will test the hypothesis that GIT1 can regulate synaptic plasticity by targeting Rac to synapses through the assembly of a signaling module comprised of Rac, PIX, and PAK that localizes in dendritic spines. Active Rac will be assayed using FRET biosensors as well as a new localization based assay that we are developing. The function of GIT1 will be determined using our library of GIT, PIX, and PAK mutants. In Specific Aim II, we will test the hypothesis that integrin signaling activates Rac in synapses. The approach is to determine whether key regulators of integrin signaling, such as FAK, Src, and MAP kinase, modulate synaptic plasticity. In Specific Aim III, we will use slice cultures from the hippocampus to extend our observation to an in vivo like environment. These studies will enhance our understanding of the molecular factors that underlie synapse formation and plasticity.

描述（由申请人提供）：突触形成和可塑性是正常认知功能（例如学习和记忆）的基础。先前的研究指出肌动蛋白动力学和粘附在突触形成和可塑性中的调节起着关键作用。这些过程可以通过 GIT1 整合在一起，GIT1 是一种最近鉴定的分子，位于海马神经元的突触前和突触后末端。 GIT1 充当结合 Rac 效应器和调节器以及其他突触分子的接头。我们的初步工作提出了可行的假设，该提案的目的是使用分离的海马神经元培养物和切片制剂严格测试特定目标中概述的这些假设。具体目标我将测试以下假设：GIT1 可以通过组装由位于树突棘的 Rac、PIX 和 PAK 组成的信号模块，将 Rac 靶向突触，从而调节突触可塑性。 Active Rac 将使用 FRET 生物传感器以及我们正在开发的新的基于定位的检测进行检测。 GIT1 的功能将使用我们的 GIT、PIX 和 PAK 突变体库来确定。在特定目标 II 中，我们将检验整合素信号传导激活突触中 Rac 的假设。该方法旨在确定整合素信号传导的关键调节因子（例如 FAK、Src 和 MAP 激酶）是否调节突触可塑性。在特定目标 III 中，我们将使用海马体切片培养物将我们的观察扩展到类似体内的环境。这些研究将增强我们对突触形成和可塑性分子因素的理解。