LASP1 signaling in dendritic spine development

树突棘发育中的 LASP1 信号传导

基本信息

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
项目类别：
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&apos 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

项目摘要

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，包含大脑中介导神经通讯的大部分兴奋性突触，并且它们在发育以及学习和记忆缺陷期间经历活动依赖性修饰。树突棘形态与突触损伤相关，这些缺陷与许多认知和退行性疾病有关，包括智力障碍、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动依赖性修饰的主要驱动力。然而，我们对脊柱结构和动力学基础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分子的功能。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作用为此，我将结合遗传和电生理学使用高分辨率活细胞成像方法和电生理学。我的研究包括以下两个总体目标：1）确定 LASP1 在突触可塑性和活动依赖性脊柱形态发生中的作用；2）检查调节 LASP1 功能的分子机制。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，因此研究树突棘中 LASP1 的功能。可能会导致对其潜在的病理生理学有更深入的了解。