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

描述（由申请人提供）：肌张力障碍是第三大最常见的运动障碍，仅次于原发性震颤和帕金森病，患病率约为330 /百万人。肌张力障碍的广泛特征是激动剂和拮抗剂肌肉同时收缩，有时持续收缩。这些共同收缩导致扭转运动和姿势，其速度、幅度和节律范围因患者而异。我们研究的总体目标是了解肌张力障碍的病理生理学。与帕金森氏病或亨廷顿病不同，神经退行性变提供了运动障碍发病机制的线索，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学。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，但对其潜在的神经元功能障碍了解甚少。此外，少数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单基因肌张力障碍的模型，为病理生理机制提供广泛的见解。我们已经确定了左旋多巴反应性肌张力障碍（DRD），作为与基底神经节功能障碍相关的肌张力障碍模型的主要候选。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，其特征是早发性全身性肌张力障碍，在给予低剂量左旋多巴（多巴胺的代谢前体）后得到改善。由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供构建，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与DRD相关的人类TH突变的敲入小鼠。因此，我们将开发并鉴定携带EA2突变的敲入小鼠。本提案的具体目标是1)开发和表征DRD敲入小鼠模型。2)对DRD敲入小鼠进行行为学表征。建立一种机制可靠且可重复的基底神经节功能障碍动物模型，对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。肌张力障碍是第三大最常见的运动障碍，患病率约为330 / 100万。肌张力障碍的广泛特征是激动剂和拮抗剂肌肉同时收缩，有时持续收缩。对肌张力障碍的病理生理机制了解甚少。因此，我们将开发和表征携带人类突变的敲入小鼠，该突变可导致左旋多巴反应性肌张力障碍，以深入了解肌张力障碍的一般病理机制。

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.