LASP1 signaling in dendritic spine development

树突棘发育中的 LASP1 信号传导

• 批准号: 8909523
• 负责人: Kenneth Myers
• 金额: $ 5.6万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8909523
• 关键词: Actin-Binding Protein; Actins; Affect; Alzheimer' s Disease; Autistic Disorder; Binding; Biochemical; Biological Process; Brain; Cell surface; Cognition Disorders; Communication; Complex; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP-Dependent Protein Kinases; Cytoskeleton; Data; Defect; Degenerative Disorder; Dendrites; Dendritic Spines; Development; Electrophysiology (science); Excitatory Synapse; F-Actin; Fluorescence Recovery After Photobleaching; Focal Adhesions; Functional disorder; Genetic; Glutamate Receptor; Glutamates; Goals; Growth; Hippocampus (Brain); Human; Impairment; Intellectual functioning disability; Investigation; Knowledge; LIM Domain; Lead; Learning; Life; Maintenance; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Mediating; Memory; Mental Retardation; Methods; Microfilaments; Modification; Molecular; Morphogenesis; Morphology; Names; Nervous System Physiology; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurons; Neurotransmitter Receptor; Phosphorylation; Phosphorylation Site; Plastics; Predisposition; Proteins; Regulation; Resolution; Risk Factors; Role; SH3 Domains; Schizophrenia; Series; Side; Signal Transduction; Signaling Protein; Site; Slice; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; Tertiary Protein Structure; Testing; Tyrosine; Vertebral column; cell motility; cellular imaging; density; design; information processing; malignant breast neoplasm; nebulin; nervous system disorder; postsynaptic; protein protein interaction; public health relevance; research study; scaffold; small hairpin RNA; therapy development; two-photon

 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.

 描述(申请人提供)：树突棘是树突上的微米大小的结构，包含大脑中大多数兴奋性突触。突触介导神经元之间的交流，在发育过程中以及学习和记忆过程中，突触都会经历依赖活动的修饰。树突棘形态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脊柱发育和活性依赖性修饰的主要驱动因素。然而，我们对脊柱结构和动力学背后的肌动蛋白机制的了解在很大程度上仍然有限。我的总体目标是确定小肌动蛋白结合蛋白LIM和SH3结构域蛋白1(LASP1)在树突棘发育和突触可塑性中的功能。为此，我将使用高分辨率活细胞成像方法和电生理学，结合遗传学和药理学方法来检测LASP1的功能。我的研究包括以下两个主要目的：1)确定LASP1在突触可塑性和活性依赖的脊椎形态发生中的作用；2)研究LASP1在脊椎中调节功能的分子机制。这项研究将使我们更好地理解树突棘发育的分子基础，对我们学习和记忆的知识具有重要的意义。此外，由于脊柱功能障碍是许多神经疾病的共同特征，研究脊椎LASP1功能可能有助于更好地了解其潜在的病理生理学。