权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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依赖性树突发育的调控机制