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Novel high-throughput screening for modifiers of TorsinA pathology

TorsinA 病理修饰因子的新型高通量筛选

基本信息

批准号：
8517913
负责人：
NICOLE CALAKOS
金额：
$ 23.55万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8517913
关键词：
Address Adult Animal Model Antibodies Behavior Bioinformatics Biological Assay Biological Preservation Cell Line Cellular biology Childhood Chimeric Proteins Collaborations Complement Core Facility Databases Defect Detection Drug Targeting Dyskinetic syndrome Dystonia Ensure Family member Fibroblasts Future Gene Targeting Genetic Genome Genomic Library Hereditary Disease Housing Human Human Cell Line Human Genome Inclusion Bodies Independent Living Induced Mutation Inherited Investigation Lead Measures Membrane Monitor Motor Movement Movement Disorders Mus Mutant Strains Mice Mutate Mutation Nature Organelles Outcome Output Pathogenesis Pathology Pathway interactions Patients Pattern Phenotype Posture Primary Dystonias Proteins RNA Interference Reagent Reporting Reproducibility Resources Scheme Signal Pathway Site-Directed Mutagenesis Spatial Distribution Structure System TOR1A gene Testing Therapeutic Time TorsinA Treatment Efficacy Triage Universities cellular pathology disease-causing mutation drug testing early childhood genome wide association study genome-wide genome-wide analysis high throughput screening improved motor disorder mouse model mutant novel novel therapeutics pre-clinical preclinical study public health relevance restoration screening small molecule therapeutic target therapy development

项目摘要

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.

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的最常见形式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理解都非常有限。人类DYT1致病突变“deltaGAG”导致膜流动的主要细胞破坏，扭转蛋白A的荧光指示剂显示不规则的点状图案（“内含物”）。我们假设，突变型扭转蛋白A引起的细胞包涵体病理学修饰剂的鉴定将提供新的靶点，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。使用我们小组最近开发的一种新的高通量检测方法，我们建议进行全基因组RNAi筛选，以使突变型TorsinA相关细胞病理正常化。我们预计，由于其全面的范围和公正的性质，这种屏幕可能会识别新的治疗候选人，并进一步建议整个信号通路，以治疗肌张力障碍为目标。