Rapsyn regulation of ACh receptor function

描述(申请人提供)：我的主要目标是确定Rapsyn如何引导神经肌肉接头(NMJ)AChR密度的增加。当NMJ受损时，会对发育和健康造成严重影响。自身免疫性疾病重症肌无力(MG)及其遗传对应的先天性肌无力综合征(CMS)导致肌肉无力和疲劳，都是由NMJ的特定成分缺陷引起的，在许多情况下包括Rapsyn。到目前为止，Rapsyn在组织培养中的分析主要是异源表达系统和异位NMJ。这些研究尚未澄清Rapsyn的功能，只是增加了关于其作用模式的争议。在野生型和突变型斑马鱼中的发现与之前的研究形成了鲜明的对比，并表明了Rapsyn-AChR相互作用的新机制。这种差异可能源于未能真正重建神经肌肉突触的模型系统的使用。为了最终确定Rapsyn在NMJ的形成和维持中的作用，我将以斑马鱼为模式脊椎动物系统来研究真正的神经肌肉连接的功能。本研究可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.