New Program Development Project

新程序开发项目

• 批准号: 8134796
• 负责人: Kimberly R Tolias
• 金额: $ 14.4万
• 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/8134796
• 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; 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

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依赖的树突状细胞发育和调控机制 可塑性 摘要 功能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位置。Rho家族GTP酶在 对这些过程进行监管。特别是，Rho GTPase Rac促进树突分枝和 脊椎的形成和维护。对RAC活性的精确时空调节对于ITS来说是至关重要的 功能，因为RAC信号异常会导致树突和棘突异常以及认知障碍 包括精神发育迟滞。尽管RAC信号很重要，但调节神经元中RAC信号的机制 保持贫乏的理解。我们之前发现RAC特异性激活剂Tiami是一种关键的调节因子 树突、棘突和突触发育。我们证明了Tiami既能调节NMDA受体，又能调节NMDA受体 EphB受体依赖的脊柱发育通过将这些受体偶联到RAC信号通路来实现 控制肌动蛋白细胞骨架重塑和蛋白质合成。最近，我们还确定了特定于RAC的 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限制了脊椎的形成和生长 树枝状结构。Tiami和BCR之间的复合体可以作为精确调节RAC的“开关” 神经元中的信号，这对于脊柱、突触和神经的正常形成和重塑是必不可少的。 树枝状结构。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 NMDA受体调节Tiami-BCR复合体，并决定其对Rac激活和 突触发育；以及3)阐明Tiami-BCR复合体在调节N-钙粘蛋白调节中的作用 突触粘连。为了解决这些问题，我们将使用多方面的方法，采用 结合了分子、细胞、生化和高分辨率成像技术。调查结果： 拟议的研究将为调节RAC激活和RAC的基本机制提供关键的见解 RAC依赖的突触和树突在神经元中的发育，并有助于阐明RAC的破坏是如何 GTPase信号会引起认知障碍，如智力低下。