Activity-dependent regulation of neuromuscular junction formation

神经肌肉接头形成的活动依赖性调节

基本信息

批准号：
8269081
负责人：
DANIEL J GOLDMAN
金额：
$ 32.36万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8269081
关键词：
Adult Applications Grants Binding Sites Biological Biological Assay Cells Choline O-Acetyltransferase Communication Complex DNA Binding Data Development Disease Elements Event Exhibits Family member Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription Genome Goals Grant HDAC4 gene Health Histone Deacetylase Indium Individual Injury Knockout Mice Mediating Molecular Muscle Muscle denervation procedure Muscle function Muscle-Specific Kinase Muscular Atrophy Mutant Strains Mice Myogenin Nature Nerve Neuromuscular Junction Nicotinic Receptors Phosphoric Monoester Hydrolases Play Protein Binding Proteins Regulation Reporting Repression Research Role Signal Transduction Skeletal Muscle Small Interfering RNA Staging Study models Synapses Synaptic Transmission Synaptic plasticity Testing Transcription Coactivator Variant aged follow-up gene induction gene repression improved in vivo injured interest knockout animal muscular structure nerve supply neuromuscular neurotransmission novel strategies postsynaptic presynaptic promoter response synaptic function synaptogenesis transcription factor

项目摘要

DESCRIPTION (provided by applicant): Synaptogenesis is regulated by both activity-dependent and independent mechanisms. Activity-dependent regulation of synaptogenesis is mediated, in part, by changes in gene expression. Therefore an important goal of neuroscientists is to understand the mechanisms by which synaptic activity is transduced to the genome to influence synapse formation. The neuromuscular junction (NMJ) is a well studied model for identifying and characterizing the mechanisms by which synaptic activity influences synapse formation and regulates gene expression. Although activity-dependent control of NMJ formation has been studied for decades, the underlying molecular mechanisms are poorly understood. We recently identified a Dach2-dependent signal transduction cascade that contributes to activity-dependent expression of nAChR and MuSK genes. Therefore, this signaling cascade along with the previously reported HDAC9 (MITR) signaling cascade, that also participates in activity-dependent nAChR gene expression, represent good candidates for mediating the effects of synaptic transmission on NMJ formation. In this grant application we propose to use a combination of genetic approaches and cell and molecular biological approaches to investigate the role Dach and MITR signaling play in regulating NMJ formation and controlling gene expression by nerve-induced muscle depolarization. Knockout animals will be used to study NMJ development, while innervated and denervated skeletal muscle will be used to study nerve-induced, activity-dependent gene regulation. Specifically, we propose to: 1) Evaluate the role Dach2 and MITR play during development of the NMJ; 2) Examine if HDAC4 coordinates Dach2 and MITR gene repression in response to muscle innervation; and 3) Determine if the Dach interacting proteins Six and Eya participate in activity-dependent regulation of gene expression. This research will identify mechanisms by which muscle activity regulates synapse formation during development and modifies synapse and muscle function in the adult. Although this research is of a basic nature, it may suggest ways of enhancing synapse formation, synaptic plasticity and muscle function in the injured, diseased or aged individual. PUBLIC HEALTH RELEVANCE: The studies in this grant application aim to understand how muscle activity signals to the genome to regulate neuromuscular development, muscle atrophy and muscle gene expression. These studies will not only further our understanding of the mechanisms underlying these events, but may also suggest novel strategies for restoring neuromuscular communication and improving muscle function following injury or disease.

描述（由申请人提供）：突触发生受活动依赖性和独立机制的调节。突触发生的活性依赖性调节是通过基因表达的变化介导的。因此，神经科学家的一个重要目标是了解突触活性转导到基因组以影响突触形成的机制。神经肌肉结（NMJ）是一个经过良好研究的模型，用于识别和表征突触活动会影响突触形成并调节基因表达的机制。尽管已经研究了数十年来研究NMJ形成的活性控制，但对基本的分子机制的了解很少。我们最近确定了DACH2依赖性信号转导级联反应，该级联反应有助于NACHR和MUSK基因的活性依赖性表达。因此，该信号传导级联以及先前报道的HDAC9（MITR）信号级联反应也参与了活动依赖性的NACHR基因表达，代表了介导突触传递对NMJ形成的影响的良好候选者。在此赠款应用中，我们建议使用遗传方法以及细胞和分子生物学方法的组合来研究DACH和MITR信号传导在调节NMJ形成和控制神经诱导的肌肉去极化基因表达中的作用。敲除动物将用于研究NMJ的发育，而神经支配和破裂的骨骼肌将用于研究神经诱导的活性依赖性基因调节。具体而言，我们建议：1）评估NMJ开发过程中DACH2和MITR的作用； 2）检查HDAC4是否会响应肌肉神经响应DACH2和MITR基因抑制； 3）确定DACH相互作用的蛋白是否参与基因表达的活性依赖性调节。这项研究将确定肌肉活动在发育过程中调节突触形成的机制，并改变成人的突触和肌肉功能。尽管这项研究具有基本的性质，但它可能提出了增强突触形成，突触可塑性和肌肉功能中受伤，患病或老年人的方法的方法。公共卫生相关性：该赠款应用中的研究旨在了解肌肉活动如何信号，以调节神经肌肉发育，肌肉萎缩和肌肉基因表达。这些研究不仅将进一步了解这些事件的机制，而且还可能提出恢复神经肌肉交流并改善损伤或疾病后肌肉功能的新策略。