Rapsyn regulation of ACh receptor function

Rapsyn 对 ACh 受体功能的调节

• 批准号: 7529206
• 负责人: Mark A Verdecia
• 金额: $ 5.2万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7529206
• 关键词: Autoimmune Diseases; Biological Models; Cholinergic Receptors; Chromosome Pairing; Congenital Myasthenic Syndromes; Defect; Development; Fatigue; Genetic; Health; Maintenance; Mediating; Mental Depression; Modeling; Muscle; Muscle Weakness; Myasthenia Gravis; Nerve; Neuromuscular Junction; Regulation; Research; Role; Synapses; System; Techniques; Tertiary Protein Structure; Testing; Zebrafish; cell motility; density; desensitization; genetic manipulation; in vivo; mutant; novel; patch clamp; peripheral membrane protein 43K; receptor; receptor function; reconstitution; stem; synaptic depression; tissue culture; tool

DESCRIPTION (provided by applicant): My main objective is to determine how rapsyn directs the increase in AChR density at the neuromuscular junction (NMJ). Severe effects on development and health result when the NMJ becomes impaired. The autoimmune disease myasthenia gravis (MG) and its genetic counterpart, congenital myasthenic syndrome (CMS), which result in muscle weakness and fatigue, are both caused by defects in specific components of the NMJ, including rapsyn in many cases. To date, analysis of rapsyn has been relegated to heterologous expression systems and ectopic NMJs in tissue culture. These studies have yet to clarify rapsyn's function and have only served to add to the controversy regarding its mode of action. Findings in wild type and mutant zebrafish stand in sharp contrast to previous research and suggest a novel mechanism for rapsyn-AChR interactions. This disparity may stem from the use of model systems that fail to authentically reconstitute neuromuscular synapses. To conclusively determined rapsyn's role in formation and maintenance of the NMJ, I will study function in true neuromuscular junctions using zebrafish as a model vertebrate system. This study may serve as a template for studies of other neuromuscular synapses.

描述（由申请人提供）：我的主要目的是确定rapsyn如何指导神经肌肉接头（NMJ）AChR密度的增加。当NMJ受损时，会对发育和健康产生严重影响。自身免疫性疾病重症肌无力（MG）及其遗传对应物，先天性肌无力综合征（CMS），导致肌肉无力和疲劳，都是由NMJ特定成分的缺陷引起的，包括在许多情况下的rapsyn。到目前为止，rapsyn的分析已被降级到异源表达系统和异位NMJ在组织培养。这些研究还没有阐明rapsyn的功能，只是增加了关于其作用方式的争议。野生型和突变斑马鱼的研究结果与以前的研究形成鲜明对比，并提出了rapsyn-AChR相互作用的新机制。这种差异可能源于使用的模型系统无法真正重建神经肌肉突触。为了最终确定rapsyn在形成和维持NMJ中的作用，我将以斑马鱼为模型脊椎动物系统研究真正的神经肌肉接头功能。本研究可作为其他神经肌肉突触研究的模板。