SYNAPTOPODIN: BIOGENESIS & PLASTICITY OF SPINE APPARATUS

突触蛋白：生物发生

• 批准号: 7382603
• 负责人: PETER H MUNDEL
• 金额: $ 27.67万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2008-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382603
• 关键词: Actin-Binding Protein; Actins; Adult; Affect; Amino Acids; Binding; Binding Sites; Biochemical; Biogenesis; Brain; Bundling; Cerebellum; Cerebral cortex; Consensus; Corpus striatum structure; Cytoskeleton; Data; Dendrites; Dendritic Spines; Electrons; Green Fluorescent Proteins; Hippocampus (Brain); Image; In Vitro; Kidney; Knock-in Mouse; Knockout Mice; Learning; Length; Link; Long-Term Potentiation; Maintenance; Memory Loss; Microfilaments; Molecular; Molecular Genetics; Morphology; Mus; Neck; Neurons; Organelles; Pathway interactions; Play; Proline; Prosencephalon; Protein Isoforms; Proteins; Radial; Rattus; Regulation; Research Personnel; Role; Site; Slice; Smooth Endoplasmic Reticulum; Surface; Synaptic plasticity; Testing; Time; Transcript; Vertebral column; Work; appendage; base; day; domain mapping; in vivo; insight; novel; olfactory bulb; podocyte; postnatal; programs; size; synaptopodin

DESCRIPTION (provided by applicant): Dendritic spines are tiny appendages on the surface of many neurons that connect excitatory afferents with dendrites. They form separate biochemical micro-compartments and are considered sites of synaptic plasticity. Many spines of forebrain neurons contains a spine apparatus, an enigmatic organelle that consists of stacks of smooth endoplasmic reticulum intervened by actin filaments containing electron-dense plates. The precise function of the spine apparatus is unknown. Synaptopodin, which was identified and characterized by the investigator, is a proline-rich actin-binding protein of telencephalic dendrites and renal podocytes. The close association with the spine apparatus suggested that synaptopodin is an important component of this organelle. Here we will explore at the molecular level how synaptopodin is mechanistically involved in the biogenesis and dynamics of the spine apparatus. Based on our Preliminary Data we hypothesize that synaptopodin is required for the formation or maintenance of the spine apparatus. Synaptopodin may affect spine apparatus morphology by bundling actin filaments in the spine neck. To test this hypothesis, we propose the following two Specific Aims: the first Specific Aim will explore the role of synaptopodin in the formation and plasticity of the spine apparatus in mice. In the second Specific Aim we will elucidate the cellular mechanism by which synaptopodin contributes to the formation and plasticity of the spine apparatus The combination of biochemical, cellular, and molecular genetic approaches proposed in this application will provide insight into the biogenesis of spine apparatus formation and its regulation by synaptopodin. If our hypotheses are correct the work proposed here will have broad significance because it will a) define a molecule link between synaptopodin function and the biogenesis and plasticity of the spine apparatus and b) establish insight into the role of the spine apparatus in synaptic plasticity. This should in the long-term enable us to develop novel therapies that tackle learning deficiencies and memory loss by modulating the expression of synaptopodin thereby promoting the cellular plasticity of the dendritic spine apparatus.

描述（申请人提供）：树突棘是许多神经元表面的微小附属物，连接兴奋性传入和树突。它们形成独立的生化微区室，被认为是突触可塑性的位点。许多前脑神经元的棘包含棘器，棘器是一种神秘的细胞器，由含有电子致密板的肌动蛋白丝介入的光滑内质网堆叠组成。脊椎器官的确切功能尚不清楚。突触足蛋白是一种富含脯氨酸的肌动蛋白结合蛋白，存在于端脑树突和肾足细胞中。与棘器的密切联系表明，synaptopodin是这个细胞器的重要组成部分。 在这里，我们将探讨在分子水平上如何synaptopodin是机械参与的生物发生和动力学的脊柱装置。基于我们的初步数据，我们假设突触足蛋白是脊柱器官形成或维持所必需的。突触足蛋白可能通过将肌动蛋白丝束在脊柱颈部而影响脊柱器官的形态。 为了验证这一假设，我们提出了以下两个具体目标：第一个具体目标将探讨突触足蛋白在小鼠脊柱器官的形成和可塑性中的作用。在第二个具体的目标，我们将阐明细胞机制，突触足蛋白有助于脊柱装置的形成和可塑性的生物化学，细胞和分子遗传学方法的组合，提出在本申请中将提供洞察脊柱装置的形成和其调节的生物起源突触足蛋白。如果我们的假设是正确的，那么本文所提出的工作将具有广泛的意义，因为它将：a）确定突触足蛋白功能与棘器的生物发生和可塑性之间的分子联系; B）建立对棘器在突触可塑性中的作用的认识。从长远来看，这将使我们能够开发新的治疗方法，通过调节突触足蛋白的表达来解决学习缺陷和记忆丧失，从而促进树突棘装置的细胞可塑性。