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New Program Development Project

新程序开发项目

基本信息

批准号：
7763457
负责人：
Kimberly R Tolias
金额：
$ 14.15万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7763457
关键词：
Actins Address Adhesions Affect Behavioral Biochemical Biological Assay Biotinylation Bipolar Disorder Brain Cadherins Cell Adhesion Cell Adhesion Molecules Cells Cognition Disorders Cognitive Complex Dendrites Dendritic Spines Development Ephrin B Receptor Excitatory Synapse Family Figs - dietary Fluorescence Resonance Energy Transfer Genetic Transcription Growth Growth and Development function Guanosine Triphosphate Phosphohydrolases Hippocampus (Brain)Homologous Protein Human Image Imaging Techniques Immunofluorescence Immunologic In Vitro Knock-out Knockout Mice Learning Link Maintenance Mediating Memory impairment Mental Retardation Mental Retardation and Developmental Disabilities Research Centers Molecular Morphogenesis Mutant Strains Mice N-Cadherin N-Methyl-D-Aspartate Receptors Nervous system structure Neurons Play Process Program Development Protein Biosynthesis Proteins RNA Interference Receptor Activation Regulation Resolution Role Signal Pathway Signal Transduction Site Staging Stimulus Surface Synapses Synaptic Receptors Syndrome Techniques Testing Vertebral column abstracting density in vivo in vivo Model inhibitor/antagonist insight member mutant nervous system development overexpression receptor coupling research study rho rho GTP-Binding Proteins spatiotemporal trafficking

项目摘要

REGULATORY MECHANISMS OF RAC-DEPENDENT DENDRITIC DEVELOPMENT AND PLASTICITY ABSTRACT Formation of a functional nervous system requires the proper development and remodeling of dendrites and dendritic spines, the primary sites of excitatory synapses in the brain. Rho family GTPases play critical roles in regulating these processes. In particular, the Rho GTPase Rac promotes dendritic arborization and the formation and maintenance of spines. Precise spatio-temporal regulation of Rac activity is essential for its function, since aberrant Rac signaling results in dendrite and spine abnormalities and cognitive disorders including mental retardation. Despite its importance, the mechanisms that regulate Rac signaling in neurons remain pooriy understood. We previously identified the Rac-specific activator Tiami as a critical regulator of dendrite, spine, and synapse development. We demonstrated that Tiami mediates both NMDA receptor-and EphB receptor-dependent spine development by coupling these receptors to Rac signaling pathways that control actin cytoskeletal remodeling and protein synthesis. Recently, we have also identified the Rac-specific inhibitor Bcr as a Tiami-interacting protein that blocks Tiami-induced Rac activation and actin remodeling. Overexpression and knockout experiments indicate that Bcr restricts the formation and growth of spines and dendrites. The complex between Tiami and Bcr may serve as an "on-off switch" for precisely regulating Rac signaling in neurons, which is essential for the proper formation and remodeling of spines, synapses, and dendrites. To test this hypothesis, we propose the following specific aims: 1) to determine the role of Bcr in restricting synapse development and dendritic growth; 2) to identify the mechanisms by which EphB and NMDA receptors regulate the Tiami-Bcr complex, and determine the consequences on Rac activation and synapse development; and 3) to elucidate the role of the Tiami-Bcr complex in regulating N-cadherinmediated synaptic adhesion. To address these questions, we will use a multifaceted approach employing a combination of molecular, cellular, biochemical, and high-resolution imaging techniques. Results from the proposed studies will provide critical insight into the fundamental mechanisms that regulate Rac activation and Rac-dependent synaptic and dendritic development in neurons, and help to elucidate how disruptions in Rac GTPase signaling give rise to cognitive disorders such as mental retardation.

RAC依赖的枝晶发育调控机制及可塑性摘要功能性神经系统的形成需要树突的适当发育和重塑，树突棘，大脑中兴奋性突触的主要部位。Rho家族GTP酶在肿瘤的发生发展中起关键作用。规范这些过程。特别地，Rho GTCRac Rac促进树突状树枝化，而Rho GTCRac Rac促进树突状树枝化。脊椎的形成和维持。Rac活性的精确时空调节对于其生物学特性至关重要。由于Rac信号传导异常导致树突和棘异常以及认知障碍，包括智力迟钝。尽管它很重要，但调节神经元中Rac信号的机制仍然不被理解。我们以前确定了Rac特异性激活剂Tiami作为一个关键的调节剂，树突、棘和突触发育。我们证明了Tiami介导NMDA受体和 EphB受体依赖性脊柱发育通过将这些受体偶联到Rac信号通路，控制肌动蛋白细胞骨架重塑和蛋白质合成。最近，我们还确定了Rac特异性抑制剂Bcr作为Tiami相互作用蛋白，阻断Tiami诱导的Rac激活和肌动蛋白重塑。过表达和敲除实验表明Bcr限制了棘的形成和生长，树突Tiami和Bcr之间的复合物可以作为精确调节Rac的“通-断开关神经元中的信号传导，这对于脊柱，突触和神经元的正确形成和重塑至关重要。树突为了验证这一假设，我们提出了以下具体目标：1）确定Bcr在限制突触发育和树突生长; 2）确定EphB和EphB的作用机制， NMDA受体调节Tiami-Bcr复合物，并决定对Rac激活的影响，阐明Tiami-Bcr复合物在调节N-钙粘蛋白介导的突触发育中的作用突触粘附为了解决这些问题，我们将采用多方面的方法，分子、细胞、生物化学和高分辨率成像技术的组合。结果拟议的研究将提供关键的洞察力，调节Rac激活的基本机制， Rac依赖的神经元突触和树突发育，并有助于阐明Rac中的破坏如何 GT3信号传导引起认知障碍，如智力迟钝。