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）：肌张力障碍是继原发性震颤和帕金森病之后第三大常见的运动障碍，患病率约为每百万人 330 人。肌张力障碍的广泛特征是主动肌和拮抗肌同时收缩，有时甚至持续收缩。这些共同收缩导致扭转运动和姿势，其速度、幅度和节奏因患者而异。我们研究的总体目标是了解肌张力障碍的病理生理学。与帕金森病或亨廷顿病的神经变性为运动障碍的发病机制提供线索不同，特发性肌张力障碍是一种功能性运动障碍，没有明显的标记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存在很强的临床病理相关性，但人们对潜在的神经元功能障碍知之甚少。此外，与基底神经节功能相关的少数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模型，以提供对病理生理机制的广泛了解。我们已经确定左旋多巴反应性肌张力障碍（DRD）作为模拟与基底神经节功能障碍相关的肌张力障碍的主要候选药物。 DRD 是由编码 GTP 环化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，服用低剂量左旋多巴（多巴胺的代谢前体）后可得到改善。 TH 突变引起的 DRD 特别适合建模，因为已经有大量的基础信息可供构建，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，我们将开发并鉴定带有与 DRD 相关的人类 TH 突变的敲入小鼠。因此，我们将开发并表征带有 EA2 突变的敲入小鼠。该提案的具体目标是 1) 开发并表征 DRD 敲入小鼠模型。 2) DRD敲入小鼠的行为特征。表现出基底神经节功能障碍的动物模型的开发和表征，其在机制上是忠实的并且可靠地可重复，对于理解肌张力障碍的病理生理学至关重要，并且对于开发新的治疗方法至关重要。肌张力障碍是第三大常见的运动障碍，患病率约为每百万人 330 人。肌张力障碍的广泛特征是主动肌和拮抗肌同时收缩，有时甚至持续收缩。对于肌张力障碍的病理生理机制知之甚少。因此，我们将开发并鉴定带有导致左旋多巴反应性肌张力障碍的人类突变的敲入小鼠，以深入了解肌张力障碍的一般病理机制。