Novel high-throughput screening for modifiers of TorsinA pathology

描述（由申请人提供）：编码torsina蛋白的TOR1A基因在遗传性原发性肌张力障碍最常见的形式DYT1中发生突变。我们对细胞生物学和治疗效果的理解对肌张力障碍都非常有限。人类DYT1致病突变“deltaGAG”导致细胞膜流动的主要细胞破坏，TorsinA的荧光指标显示不规则的间断模式（“内含物”）。我们假设，鉴定突变TorsinA蛋白引起的细胞包涵病理学修饰因子将提供新的靶点，以促进我们对肌张力障碍发病机制的理解，并为肌张力障碍的治疗提供新的靶点。利用我们小组最近开发的一种新型高通量测定方法，我们建议对使突变torsina相关细胞病理正常化的修饰剂进行全基因组RNAi筛选。我们期望这种筛查，因为它的全面范围和无偏倚的性质，可能会确定新的治疗候选人，并进一步提出整个信号通路的目标，以治疗肌张力障碍。

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.