SYNAPTOPODIN: BIOGENESIS & PLASTICITY OF 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室，被认为是突触可塑性的部位。许多前脑神经元的脊椎都有一个棘器，这是一个神秘的细胞器，由一堆堆光滑的内质网组成，中间是含有电子致密板的肌动蛋白细丝。脊椎装置的确切功能尚不清楚。研究人员鉴定的突触素是端脑树突和肾足细胞中一种富含Pro的肌动蛋白结合蛋白。与脊器的密切联系表明，突触素是该细胞器的重要组成部分。在这里，我们将在分子水平上探索突触素是如何机械地参与脊柱器官的生物发生和动力学的。根据我们的初步数据，我们假设突触素是脊器形成或维持所必需的。突触素可能通过在脊柱颈部捆绑肌动蛋白细丝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特定目标：第一个特定目标将探索突触素在小鼠脊柱器官的形成和可塑性中的作用。在第二个特定目标中，我们将阐明突触素参与脊柱器官形成和可塑性的细胞机制。本应用中提出的生化、细胞和分子遗传学方法的结合将为深入了解脊柱器官形成的生物发生及其突触素对其调控提供依据。如果我们的假设是正确的，本文提出的工作将具有广泛的意义，因为它将a)定义突触素功能与脊柱器官的生物发生和可塑性之间的分子联系，b)深入了解脊柱器官在突触可塑性中的作用。从长远来看，这将使我们能够开发新的疗法，通过调节突触素的表达来解决学习缺陷和记忆丧失，从而促进树突棘器的细胞可塑性。

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.