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

描述(申请人提供)：肌张力障碍是第三种最常见的运动障碍，仅次于特发性震颤和帕金森病，患病率为每百万人中约330人。肌张力障碍的主要特征是激动肌和拮抗肌同时收缩，有时甚至持续收缩。这些联合收缩会导致扭曲的动作和姿势，这些动作和姿势具有广泛的速度、幅度和节奏性，不同患者的情况不同。我们研究的总体目标是了解肌张力障碍的病理生理学。与帕金森病或亨廷顿病不同，神经退行性变为运动障碍的发病机制提供了线索，特发性肌张力障碍是一种功能性运动障碍，没有明显的标志物或细胞死亡来帮助定义病理生理。尽管基底神经节和肌张力障碍之间有很强的临床病理相关性，但对潜在的神经元功能障碍却知之甚少。此外，少数与基底节功能相关的肌张力障碍动物模型的价值有限，因为其病理生理学与人类肌张力障碍的异常不一致。我们解决这个问题的方法是建立一个单基因肌张力障碍的模型，以提供对病理生理机制的广泛见解。我们已经确定L-多巴反应性肌张力障碍(DRD)是模拟与基底节功能障碍相关的肌张力障碍的首选候选模型。DRD是由编码GTP环水解酶或酪氨酸羟化酶(TH)的基因突变引起的，以早发性全身性肌张力障碍为特征，经小剂量给予多巴胺的代谢前体L-多巴后有所改善。TH突变引起的DRD特别适合建模，因为已经有大量的基本信息可以建立，包括描述正常TH功能和运动控制的多巴胺能调节的大量工作。因此，我们将开发并鉴定一种携带人类TH突变的敲击小鼠，该突变与DRD相关。因此，我们将开发并鉴定一种携带EA2突变的敲门小鼠。本方案的具体目的是：1)建立并鉴定DRD的敲击性小鼠模型。2)DRD敲击小鼠的行为学特征。建立一种力学上可靠、重复性好的表现基底节功能障碍的动物模型，对于理解肌张力障碍的病理生理学和开发新的治疗方法至关重要。肌张力障碍是第三种最常见的运动障碍，患病率为每百万人中约330人。肌张力障碍的主要特征是激动肌和拮抗肌同时收缩，有时甚至持续收缩。目前对肌张力障碍的病理生理机制了解甚少。因此，我们将开发并鉴定一种携带人类突变的敲门小鼠，该突变导致L多巴反应性肌张力障碍，以提供对肌张力障碍潜在的一般病理机制的洞察。

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.