Novel high-throughput screening for modifiers of TorsinA pathology

描述(申请人提供)：编码TorsinA蛋白的TOR1A基因在最常见的遗传性原发性肌张力障碍DYT1中发生突变。我们对肌张力障碍的细胞生物学和治疗效果的了解都非常有限。人类DYT1致病突变“deltaGAG”会导致细胞膜流动的重大破坏，TorsinA的荧光指示器显示出不规则的点状图案(“包涵体”)。我们推测，由突变的TorsinA蛋白引起的细胞包涵体病理修饰物的鉴定将为促进我们对肌张力障碍发病机制的理解和为肌张力障碍的治疗提供新的靶点。使用我们团队最近开发的一种新的高通量分析，我们建议进行全基因组RNAi筛选，以寻找使突变的TorsinA相关细胞病理正常化的修饰物。我们期望，由于其全面的范围和不偏不倚的性质，这一筛选可以识别新的候选治疗方法，并进一步建议将整个信号通路作为治疗肌张力障碍的靶点。

DESCRIPTION (provided by applicant): The TOR1A gene encodingTorsinA protein is mutated in the most common form of inherited primary dystonia, DYT1. Both our understanding of the cellular biology and efficacy of treatments is very limited for dystonia. The human DYT1 disease-causing mutation, "deltaGAG" causes major cellular disruption of membrane flow and fluorescent indicators of TorsinA show an irregular punctuate pattern ("inclusions"). We hypothesize that the identification of modifiers of cellular inclusion pathology caused by mutant TorsinA proteins will provide novel targets to advance both our understanding of dystonia pathogenesis and to provide novel targets for the treatment of dystonia. Using a novel high-throughput assay that our group recently developed, we propose to perform whole genome RNAi screening for modifiers that normalize mutant TorsinA-associated cellular pathology. We expect that this screen because of its comprehensive scope and unbiased nature may identify novel therapeutic candidates and further suggest entire signaling pathways to target for the treatment of dystonia.