Rapsyn regulation of ACh receptor function

描述（由申请人提供）：我的主要目标是确定rapsyn如何指导神经肌肉交界处（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）及其遗传对应的先天性重症肌无力综合征（CMS）导致肌肉无力和疲劳，两者都是由NMJ的特定成分缺陷引起的，在许多情况下包括rapsyn。迄今为止，rapsyn的分析已经降级到组织培养中的异源表达系统和异位NMJs。这些研究尚未阐明rapsyn的功能，只是增加了关于其作用方式的争议。野生型和突变型斑马鱼的研究结果与先前的研究结果形成鲜明对比，并提出了rapsyn-AChR相互作用的新机制。这种差异可能源于模型系统的使用不能真实地重建神经肌肉突触。为了最终确定rapsyn在NMJ形成和维持中的作用，我将以斑马鱼为模型脊椎动物系统研究真实神经肌肉连接的功能。这项研究可以作为研究其他神经肌肉突触的模板。

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.