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

描述（由申请人提供）：Charcot Marie Tooth disease （CMT）是美国最常见的遗传性周围神经病变。患有CMT的个体会经历一系列的症状，从轻微的运动协调性丧失和一些肌肉无力到令人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，与其他周围神经元疾病如肌萎缩性侧索硬化症（ALS； 434项NIH资助）相比，CMT的资金相对不足（在关键词搜索中确定了65项NIH资助）。在本提案中，我们开发并表征了一种新的CMT小鼠模型，该模型携带在CMT的遗传形式中发现的人类动力蛋白突变。动力蛋白是一种重要的分子马达，其功能是沿神经轴突运输货物。其他几种人类动力蛋白突变最近被证明会引起其他神经系统疾病，这表明对动力蛋白的研究将在未来变得非常重要。我们建议在敲入小鼠中表征人类动力蛋白疾病等位基因，以检查疾病发生和进展的机制。该提案的第一个目的是通过一系列行为分析来表征突变小鼠系中CMT疾病的发病和进展，这些行为分析检查了人类CMT常见的表型。在第二个目标中，我们将检查突变小鼠株中动力蛋白的生化和生物物理特性。在第三个目标中，我们分析了相关神经元货物的细胞内运输。通过将行为表型与突变动力蛋白的分子特征和细胞运输分析相关联，我们希望对动力蛋白在神经系统疾病中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.