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：
8634153
负责人：
NICOLE CALAKOS
金额：
$ 19.43万
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/8634153
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）：TOR1A基因编码的蛋白是以最常见的遗传原发性肌张力障碍Dyt1的最常见形式突变的。我们对细胞生物学的理解和治疗的功效都受到肌张力障碍的限制。人类Dyt1疾病的突变“ Deltagag”导致膜流量的严重细胞破坏和Torsina的荧光指标表现出不规则的点点符号模式（“夹杂物”）。我们假设，由突变体torsina蛋白引起的细胞包容病理学修饰剂的鉴定将提供新的靶标，以促进我们对肌张力障碍发病机理的理解，并为肌张力障碍治疗提供新的靶标。使用我们小组最近开发的新型高通量测定法，我们建议对修饰剂进行整个基因组RNAI筛选，以使突变体Torsina相关的细胞病理标准化。我们预计，由于其全面的范围和无偏见的性质，因此该屏幕可能会识别出新的治疗候选者，并进一步提出整个信号传导途径，以靶向肌张力障碍的治疗。