Activity-dependent regulation of neuromuscular junction formation

神经肌肉接头形成的活动依赖性调节

• 批准号: 7729761
• 负责人: DANIEL J GOLDMAN
• 金额: $ 33.08万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729761
• 关键词: Adult; Applications Grants; Binding Sites; Biological; Biological Assay; 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; 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; public health relevance; response; synaptogenesis; transcription factor

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）：突触发生受活性依赖性和独立性机制调节。突触发生的活动依赖性调节部分由基因表达的变化介导。因此，神经科学家的一个重要目标是了解突触活动被传递到基因组以影响突触形成的机制。神经肌肉接头（NMJ）是一个研究得很好的模型，用于识别和表征突触活动影响突触形成和调节基因表达的机制。虽然NMJ形成的活性依赖性控制已经研究了几十年，但对其潜在的分子机制知之甚少。我们最近确定了一个Dach 2依赖的信号转导级联，有助于活性依赖性表达的nAChR和MuSK基因。因此，该信号级联沿着先前报道的HDAC 9（MITR）信号级联，其也参与活性依赖性nAChR基因表达，代表用于介导突触传递对NMJ形成的影响的良好候选者。在这项授权申请中，我们建议使用遗传方法和细胞及分子生物学方法的组合来研究Dach和MITR信号在调节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发育，而受神经支配和去神经支配的骨骼肌将用于研究神经诱导的活性依赖性基因调控。具体而言，我们建议：1）评估Dach 2和MITR在NMJ发育过程中的作用; 2）检查HDAC 4是否响应于肌肉神经支配而协调Dach 2和MITR基因抑制;以及3）确定Dach相互作用蛋白Six和Eya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，并在成人中改变突触和肌肉功能。虽然这项研究是一个基本的性质，它可能会建议的方法，以加强突触的形成，突触可塑性和肌肉功能的受伤，患病或老年人。公共卫生关系：这项研究旨在了解肌肉活动如何向基因组发出信号，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加深我们对这些事件背后机制的理解，而且还可能为恢复神经肌肉沟通和改善损伤或疾病后的肌肉功能提出新的策略。