LASP1 signaling in dendritic spine development

 描述（由申请人提供）：树突棘是树突上的微米级结构，包含大脑中的大多数兴奋性突触。突触介导神经元通讯，并且它们在发育以及学习和记忆期间经历活动依赖性修饰。树突棘形态的缺陷与突触损伤相关。因此，这些缺陷与许多认知和退行性疾病有关，包括智力残疾、精神分裂症和阿尔茨海默病。肌动蛋白细胞骨架的动态重塑是棘发育和活性依赖性修饰的主要驱动力。然而，我们对脊椎结构和动力学的肌动蛋白机制的理解仍然很有限。我的总体目标是确定小肌动蛋白结合蛋白，LIM和SH 3结构域蛋白1（LASP 1），在树突棘发育和突触可塑性的功能。为此，我将使用高分辨率活细胞成像方法和电生理学结合遗传和药理学方法来检查LASP 1功能。我的研究包括以下两个总体目标：1）确定LASP 1在突触可塑性和活动依赖性棘形态发生中的作用; 2）研究调节LASP 1在棘中功能的分子机制。这项研究将导致更好地了解树突棘发育的分子基础，对我们的学习和记忆知识具有重要意义。此外，由于脊柱功能障碍是许多神经系统疾病的共同特征，因此研究LASP 1在脊柱中的功能可能有助于更好地了解其潜在的病理生理学。

 DESCRIPTION (provided by applicant): Dendritic spines are micron-sized structures on dendrites that contain the majority of excitatory synapses in the brain. Synapses mediate neuronal communication, and they undergo activity- dependent modifications during development as well as during learning and memory. Defects in the morphology of dendrite spine morphology are correlated with synaptic impairment. Consequently, these defects are associated with numerous cognitive and degenerative disorders, including intellectual disability, schizophrenia, and Alzheimer's disease. Dynamic remodeling of the actin cytoskeleton is the primary driver of spine development and activity- dependent modifications. However, our understanding of the actin mechanisms underlying spine structure and dynamics remain largely limited. My overall goal is to determine the function of the small actin-binding protein, LIM and SH3 domain protein 1 (LASP1), in dendritic spine development and synaptic plasticity. To that end, I will use high resolution live-cell imaging approaches and electrophysiology in combination with genetic and pharmacological methods to examine LASP1 function. My investigation includes the following two general aims: 1) determine the role of LASP1 in synaptic plasticity and activity-dependent spine morphogenesis; and 2) examine the molecular mechanisms regulating LASP1 function in spines. This study will lead to a greater understanding of the molecular underpinnings of dendritic spine development, with important implications for our knowledge of learning and memory. In addition, because spine dysfunction is a common feature of many neurological disorders, investigating LASP1 function in spines may lead to a greater understanding of their underlying pathophysiology.