Generation of Mouse Models for Early Onset Dystonia

早发性肌张力障碍小鼠模型的生成

• 批准号: 6803360
• 负责人: Laurie J. Ozelius
• 金额: $ 22.64万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6803360
• 关键词: adenosinetriphosphatase; developmental neurobiology; disease /disorder model; disease /disorder onset; dopamine; dystonia; genetically modified animals; laboratory mouse; model design /development; molecular pathology; neurochemistry; neurogenetics; neuromuscular function; neuropathology; protein structure function

Early onset torsin dystonia is a movement disorder inherited in an autosomal dominant manner with reduced penetrance (30-40%). Most cases of the disease are caused by a 3 base pair deletion in the DYT1 (TOR1A) gene however we have recently described a family with an 18 base pair deletion in this same gene. The mechanism(s) underlying dystonia remain elusive however the defect(s) is thought to involve the basal ganglia with evidence from multiple forms of dystonia as well as more recent data from this PO1 implicating alterations in dopaminergic metabolism in the pathogenesis of dystonia. With the discovery of the DYT1 gene, we can now generate mouse models specific to this disorder to explore the mechanism of disease. In the previous cycle, we have created transgenic (tg) animals that overexpress either the wild-type (wt) or GAG deletion (delta E) mutation under the control of a strong promoter (CMV). Preliminary results suggest that these mice have a defect in motor learning as tested on the rotorod. In addition, we have produced tetracycline inducible bigenic mice that express either the wt or GAG deletion specifically in neurons that are being assessed. In this application, we will use these models and generate additional genetically modified animals to determine the normal function of the DYT1 gene product and whether the disease is caused by a gain or loss of function. In addition, we will address whether the dopaminergic system is involved in DYT1 dystonia by selectively knocking-ont or over-expressing the DYT1 gene in dopaminergic neurons. All mice generated in this Project will be evaluated for neurologic and motoric phenotypes and undergo neurochemical and neuropathological analyses during development (Project 2) and adulthood (Project 1). The mice will also be available for testing genetic modifiers discovered in Project 3. The generation of these mice should lead to clues about the function of this gene (DYT1) and eventually to viable therapies for this disease.

早发性扭转性肌张力障碍是一种以常染色体显性遗传方式遗传的运动障碍，伴运动障碍率降低（30-40%）。大多数病例是由DYT 1（TOR 1A）基因中的3个碱基对缺失引起的，然而我们最近描述了一个在同一基因中有18个碱基对缺失的家族。肌张力障碍的潜在机制仍然难以捉摸，但是认为缺陷涉及基底神经节，证据来自多种形式的肌张力障碍以及来自该PO 1的更近期数据，表明肌张力障碍发病机制中多巴胺能代谢的改变。随着DYT 1基因的发现，我们现在可以产生这种疾病的特异性小鼠模型来探索疾病的机制。在前一个周期中，我们已经创建了在强启动子（CMV）控制下过表达野生型（wt）或GAG缺失（Δ E）突变的转基因（tg）动物。 初步结果表明，这些小鼠在旋转杆上测试时有运动学习缺陷。此外，我们已经产生了四环素诱导的双基因小鼠，其在正在评估的神经元中特异性表达wt或GAG缺失。在本申请中，我们将使用这些模型并产生额外的转基因动物，以确定DYT 1基因产物的正常功能以及疾病是否由DYT 1基因产物的获得或丧失引起。 功能此外，我们将通过选择性敲除或过表达多巴胺能神经元中的DYT 1基因来解决多巴胺能系统是否参与DYT 1肌张力障碍。将对本项目中产生的所有小鼠进行神经和运动表型评价，并在发育（项目2）和成年（项目1）期间进行神经化学和神经病理学分析。这些小鼠也将用于测试基因修饰剂 在Project 3中发现。这些小鼠的产生应该会导致有关该基因（DYT 1）功能的线索，并最终导致这种疾病的可行疗法。