Development and characterization of a novel dynein mutant mouse model of CMT

描述(申请人提供)：Charcot Marie Tooth病(CMT)是美国最常见的遗传性周围神经病。患有CMT的患者会出现一系列症状，从轻微的运动协调性丧失和一些肌肉无力到衰弱的疼痛和肌肉无力，通常导致需要治疗干预。令人惊讶的是，与肌萎缩侧索硬化症(ALS)等其他外周神经元疾病相比，CMT的资金相对不足(在关键字搜索中发现了65笔NIH活跃赠款)(已确定434笔NIH活跃赠款)。在这项建议中，我们开发并表征了一种新的CMT小鼠模型，该模型携带在遗传性CMT中发现的人类动力蛋白突变。动力蛋白是一种基本的分子马达，其功能是沿着神经轴突运输货物。最近，其他几个人类动力蛋白突变被证明会导致其他神经疾病，这表明对动力蛋白的研究在未来将变得非常重要。我们建议在敲入鼠身上鉴定一种人类动力蛋白疾病等位基因，以研究疾病发生和发展的机制。该提案的第一个目标是通过一系列行为分析来表征CMT疾病在突变小鼠系中的发生和发展，这些行为分析检查人类CMT常见的表型。在第二个目标中，我们将检查动力蛋白在突变小鼠品系中的生化和生物物理性质。在第三个目标中，我们分析了相关神经元的细胞内运输。通过将行为表型与突变的动力蛋白和细胞转运分析的分子特征相关联，我们希望对动力蛋白在神经系统疾病中所起的关键作用有更全面的了解，最终导致更好的人类治疗方法，包括潜在的药物干预策略。

DESCRIPTION (provided by applicant): Charcot Marie Tooth disease (CMT) is the most common inheritable peripheral neuropathy in the United States. Individuals with CMT experience a range of symptoms, ranging from mild loss of motor coordination and some muscle weakness to debilitating pain and muscle weakness, often leading to the need for therapeutic intervention. Surprisingly, CMT is relatively underfunded (65 active NIH grants identified in a keyword search) compared to other peripheral neuron diseases such as amyotrophic lateral sclerosis (ALS; 434 active NIH grants identified). In this proposal we develop and characterize a novel CMT mouse model that carries a human dynein mutation found in a hereditary form of CMT. Dynein is an essential molecular motor that functions to transport cargos along nerve axons. Several other human dynein mutations have recently been shown to cause other neurological disorders, suggesting that the study of dynein will become highly important in the future. We propose to characterize a human dynein disease allele in knock-in mice to examine the mechanism of disease onset and progression. The first aim of the proposal is to characterize CMT disease onset and progression in the mutant mouse line with a battery of behavioral assays that examine phenotypes common to human presentation of CMT. In the second aim, we will examine the biochemical and biophysical properties of dynein in the mutant mouse strain. In the third aim we analyze intracellular transport of relevant neuronal cargoes. By correlating the behavioral phenotypes with the molecular characterization of the mutant dynein and cellular transport assays, we hope to generate a more comprehensive understanding of the key role dynein plays in neurological disease, ultimately leading to better human therapeutics including potential drug intervention strategies.