Generation of a mouse model of L-DOPA-responsive dystonia (DRD)

L-DOPA 反应性肌张力障碍 (DRD) 小鼠模型的生成

• 批准号: 7765651
• 负责人: ELLEN J. HESS
• 金额: $ 19.53万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7765651
• 关键词: Agonist; Animal Model; Basal Ganglia; Behavioral; Cell Death; Clinical; Development; Dopamine; Dose; Dystonia; Dystonic Disorder; Essential Tremor; Exhibits; Functional disorder; GTP Cyclohydrolase; Generations; Genes; Goals; Human; Huntington Disease; Metabolic; Modeling; Molecular; Motor; Movement; Movement Disorders; Mus; Muscle; Muscle Contraction; Mutation; Nature; Nerve Degeneration; Neuronal Dysfunction; Parkinson Disease; Pathogenesis; Patients; Periodicity; Phenotype; Posture; Prevalence; Range; Regulation; Research; Risk; Speed; Tyrosine 3-Monooxygenase; Work; base; behavior test; design; early onset; expectation; human disease; insight; motor control; mouse model; nervous system disorder; novel therapeutics; tool

DESCRIPTION (provided by applicant): Dystonia is the third most common movement disorder, after essential tremor and Parkinson disease, with a prevalence of ~330 per million. Dystonia is broadly characterized by simultaneous and sometimes sustained contractions of agonist and antagonist muscles. These co-contractions result in twisting movements and postures that have a wide range of speed, amplitude and rhythmicity that varies among patients. The general goal of our research is to understand the pathophysiology of dystonia. Unlike Parkinson disease or Huntington disease where neurodegeneration provides clues to the pathogenesis of the movement disorder, idiopathic dystonia is a functional movement disorder without obvious markers or cell death to help define pathophysiology. Despite a strong clinico-pathological correlation between the basal ganglia and dystonia, there is little understanding of the underlying neuronal dysfunction. Moreover, the few animal models of dystonia associated with basal ganglia function are of limited value because the pathophysiology is inconsistent with abnormalities in human dystonias. Our approach to this problem is to model a monogenic dystonic disorder to provide broad insight into pathophysiological mechanisms. We have identified L-DOPA responsive dystonia (DRD), as a leading candidate for modeling dystonia associated with basal ganglia dysfunction. DRD is caused by mutations in genes encoding either GTP cyclohydrolase or tyrosine hydroxylase (TH) and is characterized by early onset generalized dystonia that is ameliorated after administration of low doses of L-DOPA, the metabolic precursor of dopamine. DRD caused by mutations in TH is particularly amenable for modeling because there is already a wealth of basic information on which to build, including an enormous body of work describing normal TH function and dopaminergic regulation of motor control. Therefore, we will develop and characterize a knockin mouse bearing a human mutation in TH that is associated with DRD. Therefore, we will develop and characterize a knockin mouse bearing an EA2 mutation. The specific aims of this proposal are 1) to develop and characterize a knockin mouse model of DRD. 2) To behaviorally characterize the DRD knockin mice. Development and characterization of an animal model exhibiting basal ganglia dysfunction that is mechanistically faithful and reliably reproducible is critical to understanding pathophysiology in dystonia and essential for developing novel therapeutics. Dystonia is the third most common movement disorder with a prevalence of ~330 per million. Dystonia is broadly characterized by simultaneous and sometimes sustained contractions of agonist and antagonist muscles. There is little understanding of the pathophysiological mechanisms underlying dystonia. Therefore, we will develop and characterize a knockin mouse bearing a human mutation that causes L-DOPA-responsive dystonia to provide insight into general pathomechanisms underlying dystonia.

描述（由申请人提供）：肌张力障碍是仅次于本质震颤和帕金森氏病的第三大最常见的运动障碍，其患病率为约330百万。肌张力障碍的特征是激动剂和拮抗剂肌肉的同时且有时持续的收缩。这些共缩合会导致运动和姿势的扭曲运动和姿势在患者之间有各种速度，振幅和节奏性。我们研究的一般目标是了解肌张力障碍的病理生理学。与帕金森氏病或亨廷顿疾病不同，神经变性为运动障碍的发病机理提供了线索，特发性肌张力障碍是一种功能运动障碍，没有明显的标记或细胞死亡，以帮助定义病理生理学。尽管基底神经节和肌张力障碍之间存在很强的临床病理学相关性，但对潜在的神经元功能障碍的了解很少。此外，与基底神经节功能相关的肌张力障碍动物模型的价值有限，因为病理生理学与人肌张力障碍的异常不一致。我们解决这个问题的方法是对单基因肌疾病进行建模，以提供对病理生理机制的广泛见解。我们已经确定了L-DOPA反应性肌张力障碍（DRD），是对基底神经节功能障碍相关的肌张力障碍的领先候选者。 DRD是由编码GTP环氢酶或酪氨酸羟化酶（TH）的基因突变引起的，其特征是早期发作普遍性肌张力纳病，在给药低剂量的L-DOPA（多巴胺的代谢前体）后，这些肌张力蛋白会得到改善。由TH突变引起的DR尤其适合建模，因为已经有大量的基本信息可以构建，包括描述正常TH功能和多巴胺能调节运动控制的大量工作。因此，我们将发展并表征与DRD相关的人类突变的敲击小鼠。因此，我们将发展并表征具有EA2突变的敲击小鼠。该提案的具体目的是1）开发和表征DRD的敲蛋白小鼠模型。 2）在行为上表征了DRD敲击蛋白小鼠。在机械上忠实且可靠地再现的动物模型的开发和表征对于理解肌张力障碍的病理生理学至关重要，对于发展新型疗法至关重要。肌张力障碍是第三大常见的运动障碍，每百万个患病率约为330。肌张力障碍的特征是激动剂和拮抗剂肌肉的同时且有时持续的收缩。对肌张力障碍的病理生理机制几乎没有理解。因此，我们将开发并表征具有人类突变的敲击小鼠，该突变会导致L- dopa反应性肌张力障碍提供对肌张力障碍基础的一般病理机制的见解。