Novel Genetic Mouse Model to Study the Consequences of TorsinA Dysfunction

研究 TorsinA 功能障碍后果的新型基因小鼠模型

基本信息

批准号：
8114531
负责人：
NICOLE CALAKOS
金额：
$ 23.08万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8114531
关键词：
ATP phosphohydrolase Acetylcholine Acute Adverse effects Animal Model Animals Area Behavior Behavioral Biochemical Biological Assay Biology Brain Brain Pathology Brain region Complement Computer Simulation Corpus striatum structure Cultured Cells Data Defect Development Disease Dopamine Dystonia Evaluation Exploratory/Developmental Grant Focal Dystonias Functional disorder Future GAG Gene Genes Genetic Goals Human In Vitro Inclusion Bodies Individual Inherited Involuntary Movements Knowledge Learning Longevity Methods Modality Modeling Moods Motor Movement Disorders Mus Mutant Strains Mice Mutation Neurodegenerative Disorders Neurologic Neuronal Dysfunction Neurons Neurotransmitters Other Genetics Pathogenesis Pathology Patients Phenotype Proteins Role Sensory Site Slice Specimen Sporadic Dystonias Surveys Synaptic plasticity System TOR1A gene Techniques Testing TorsinA Transgenic Organisms Ubiquitin Variant aged base behavior test behavioral impairment disability early onset in vitro Assay in vivo insight loss of function motor learning mouse model mutation carrier nervous system disorder neuropathology neurotransmission novel overexpression protein function protein structure prediction tool

项目摘要

DESCRIPTION (provided by applicant): Dystonia is among the top 3 prevalent movement disorders and a cause of unremitting disability from a relatively young onset. As yet, its mechanisms are largely unknown. It is not considered a neurodegenerative disease and abnormalities in brain plasticity are suggested. In a patient with sporadic, late-onset, focal dystonia, we recently identified a novel rare sequence variant of TOR1A (p.F205I). TOR1A mutation is a known cause of familial early-onset, generalized dystonia (DYT1, c.GAG). After revealing in silico and in vitro evidence that the p.F205I variant impairs TorsinA function, we developed a knockin mutation mouse model to test the behavioral significance. In preliminary studies, we have found that F205I mutant mice have robust and replicable behavioral abnormalities in a motor learning task. We propose to further develop this novel mouse model and use it to understand the changes in brain activity and neuropathology due to F205I TorsinA and their relationship to behavior. The F205I TOR1A mouse model provides a useful tool to establish the causal relationship between TorsinA dysfunction, neuronal pathology and altered behavior. By furthering knowledge of TorsinA biology, we hope to accelerate insights for the treatment of dystonia. PUBLIC HEALTH RELEVANCE: Dystonia is an involuntary movement disorder that is a cause of significant disability. The pathogenesis of dystonia remains unclear. Consequently, current treatment modalities have both limited efficacy and significant side effects. We propose to develop a novel animal model based on a rare TOR1A sequence variant identified in an individual with late-onset, focal dystonia. This novel mouse model has the potential to provide critical insights into the relationship between TorsinA dysfunction and behavioral sequelae. These studies will advance our understanding of the contribution of this gene to dystonia and related neurological diseases.

描述（由申请人提供）：肌张力障碍是最常见的 3 种运动障碍之一，也是导致从相对年轻的发病开始就持续残疾的原因。迄今为止，其机制在很大程度上尚不清楚。它不被认为是一种神经退行性疾病，并且表明大脑可塑性异常。在一位患有散发性、迟发性、局灶性肌张力障碍的患者中，我们最近发现了 TOR1A (p.F205I) 的一种新的罕见序列变异。 TOR1A 突变是家族性早发性全身性肌张力障碍（DYT1、c.GAG）的已知原因。在通过计算机和体外证据揭示 p.F205I 变体损害 TorsinA 功能后，我们开发了敲入突变小鼠模型来测试行为意义。在初步研究中，我们发现F205I突变小鼠在运动学习任务中具有稳健且可复制的行为异常。我们建议进一步开发这种新型小鼠模型，并用它来了解 F205I TorsinA 引起的大脑活动和神经病理学变化及其与行为的关系。 F205I TOR1A 小鼠模型为建立 TorsinA 功能障碍、神经元病理和行为改变之间的因果关系提供了有用的工具。通过进一步加深对 TorsinA 生物学的了解，我们希望加快对肌张力障碍治疗的认识。公共卫生相关性：肌张力障碍是一种不自主运动障碍，是导致严重残疾的原因。肌张力障碍的发病机制仍不清楚。因此，目前的治疗方式疗效有限且副作用显着。我们建议开发一种新的动物模型，该模型基于在迟发性局灶性肌张力障碍个体中发现的罕见 TOR1A 序列变异。这种新颖的小鼠模型有可能为 TorsinA 功能障碍和行为后遗症之间的关系提供重要的见解。这些研究将增进我们对该基因对肌张力障碍和相关神经系统疾病的影响的理解。