Genetic Modeling for SMA Therapeutic Pathways

描述(申请人提供)：脊髓性肌萎缩症(SIVIA)是一种毁灭性的遗传性神经退行性疾病，由于神经肌肉接头(NMJ)功能障碍而导致进行性运动功能丧失，最终导致运动神经元丧失。SMA是由运动神经元存活丧失(SMN1)引起的，SMN1是核Gmin复合体的一个组成部分，被认为介导SnRNP复合体的组装和运输，从而控制关键突触蛋白的合成和传递。然而，SMN相关靶基因的识别和功能以及SMN在NMJ中的确切分子作用在很大程度上仍然是一个谜。拟议的项目重点将是使用简单的遗传模型系统来剖析SMN控制突触形态和功能的机制(S)，从而确定可能的干预靶点，以减轻哺乳动物模型或人类患者的SMA。我们将在果蝇中使用遗传学方法来确定SMN突变的功能修饰物，并将在果蝇和线虫(Artavanis-Tsakonas、van Veter和Hart实验室)中研究它们。哺乳动物细胞分析(鲁宾实验室)将扩展和证实无脊椎动物的研究，而哺乳动物细胞中确定的可能的功能关系和药物干预将使用线虫和果蝇提供的复杂遗传工具进行测试。每个系统都有独特的实验优势，所提出的对脊椎动物和无脊椎动物的分析集成为深入了解SMN生物学和病理学提供了特殊的前景，同时，重要的是，它带来了确定新的治疗途径的前景。

DESCRIPTION (provided by applicant): Spinal Muscular Atrophy (SIVIA) is a devastating inherited neurodegenerative disease causing progressive loss of motor functions due to malfunction of neuromuscular junctions (NMJs) and eventual loss of motor neurons. SMA is caused by loss of Survival of Motor Neuron (SMN1), a component of the nuclear gemin complex which is thought to mediate assembly and transport of snRNP complexes and thus control the synthesis and delivery of key synaptic proteins. However, the identity and function of relevant SMN target genes and the precise molecular role of SMN at the NMJ remain largely a mystery. The proposed project focus will be to use simple genetic model systems to dissect the mechanism(s) by which SMN controls synaptic form and function, and thus identify likely targets for interventions to attenuate SMA in mammalian models or human patients. We will be using genetic approaches in Drosophila to identify functional modifiers of SMN mutations and will study them in both Drosophila as well as C.elegans (Artavanis-Tsakonas, van Vactor and Hart Laboratories). Mammalian cell assays (Rubin laboratory) will extend and corroborate the studies in invertebrates while possible functional relationships and pharmacological interventions identified in mammalian cells will be tested using the sophisticated genetic tools that C elegans and Drosophila offer. Each system has unique experimental advantages and the integration of the proposed analysis across vertebrates and invertebrates offers exceptional promise for an in depth understanding of SMN biology and pathology while, importantly, it carries the promise of identifying novel therapeutic avenues.