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（由应用程序提供）：树突状刺是树突上的微米大小结构，其中包含大脑中大部分兴奋性突触。突触中位神经元交流，并在发展和记忆过程中进行活动依赖性修改。树突形态形态的形态缺陷与合成障碍相关。因此，这些缺陷与许多认知和退化性疾病有关，包括智力障碍，精神分裂症和阿尔茨海默氏病。肌动蛋白细胞骨架的动态重塑是脊柱发育和活动依赖性修饰的主要驱动力。但是，我们对脊柱结构和动力学基础机制的理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域蛋白1（LASP1）在树突状脊柱发育和突触可塑性中的功能。为此，我将使用高分辨率的实时成像方法和电生理学结合遗传和药物方法来检查LASP1功能。我的研究包括以下两个一般目的：1）确定LASP1在突触可塑性和活性依赖性脊柱形态发生中的作用； 2）检查调节刺中LASP1功能的分子机制。这项研究将使对树突状脊柱发育的分子基础有更多的了解，这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常见特征，因此研究棘的LASP1功能可能会导致对其潜在的病理生理学有更多的了解。