New Program Development Project

新程序开发项目

• 批准号: 8318654
• 负责人: Kimberly R Tolias
• 金额: $ 14.42万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 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/8318654
• 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; Developmental Disabilities; Ephrin B Receptor; Excitatory Synapse; Family; 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; Intellectual functioning disability; Knock-out; Knockout Mice; Learning; Link; Maintenance; Mediating; Memory impairment; Mental Retardation; 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; Research; 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

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依赖性树突发展的监管机制和 可塑性 抽象的 功能神经系统的形成需要对树突的适当发展和重塑， 树突状刺，大脑兴奋性突触的主要部位。 Rho Family GTPases在 调节这些过程。特别是，Rho GTPase RAC促进了树突状树皮化和 刺的形成和维护。 RAC活动的精确时空调节对于其 功能，因为异常的RAC信令导致树突和脊柱异常和认知障碍 包括智力低下。尽管其重要性，但调节RAC信号的机制在神经元中 保持贫困。我们先前以前将RAC特异性激活剂Tiami确定为关键调节剂 树突，脊柱和突触发育。我们证明了Tiami介导了两个NMDA受体，并且 通过将这些受体耦合到RAC信号通路，EPHB受体依赖性脊柱发育 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特定的 抑制剂BCR作为tiami相互作用的蛋白质，可阻断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限制了刺和生长的形成和生长 树突。 Tiami和BCR之间的复合物可以用作精确调节RAC的“开关开关” 神经元中的信号传导，这对于刺，突触和重塑的正确形成和重塑至关重要 树突。为了检验这一假设，我们提出以下特定目的：1）确定BCR在 限制突触的发展和树突生长； 2）确定EPHB和EPHB的机制 NMDA受体调节tiami-BCR复合物，并确定对RAC激活的后果和 突触发展； 3）阐明tiami-BCR复合物在调节N-辅助介导的作用 突触粘附。为了解决这些问题，我们将使用一种多方面的方法 分子，细胞，生化和高分辨率成像技术的组合。结果 拟议的研究将对调节RAC激活和 依赖RAC的神经元中的突触和树突状发展，并有助于阐明RAC中的破坏 GTPase信号传导引起了认知障碍，例如智力障碍。