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

新型 CMT 动力蛋白突变小鼠模型的开发和表征

• 批准号: 8808189
• 负责人: STEPHEN J KING
• 金额: $ 21.34万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8808189
• 关键词: Address; Affect; Alleles; Amino Acids; Amyotrophic Lateral Sclerosis; Animals; Arginine; Asians; Axon; Behavioral; Behavioral Assay; Biochemical; Biological Assay; Biological Models; Cells; Charcot-Marie-Tooth Disease; Clinical; Country; Data; Defect; Development; Disease; Disease Progression; Dynein ATPase; Family; Future; Gait abnormality; Generations; Genes; Goals; Grant; Health; Health system; Histidine; Human; Individual; Inherited; Intervention; Intracellular Transport; Knock-in Mouse; Laboratory Study; Learning; Link; Loa; Lower Extremity; Mental Retardation; Molecular; Molecular Motors; Motor; Motor Skills; Mus; Muscle Weakness; Mutant Strains Mice; Mutation; Nerve; Neurons; Neuropathy; Onset of illness; Pain; Peripheral; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phenotype; Play; Population; Risk; Sensory; Spinal Muscular Atrophy; Structure; Symptoms; Talipes cavus; Testing; Therapeutic; Therapeutic Intervention; United States; United States National Institutes of Health; Work; biophysical properties; brain tissue; disease phenotype; effective therapy; experience; human disease; mouse model; mutant; mutant mouse model; nervous system disorder; novel; public health relevance; research study; response; wasting

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.

描述（由申请人提供）：Charcot玛丽牙病（CMT）是美国最常见的遗传性周围神经病变。患有CMT的个体经历一系列症状，从轻度运动协调丧失和一些肌肉无力到使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侧索硬化症（ALS;确定了434个有效的NIH赠款金）相比，CMT的资金相对不足（在关键词搜索中确定了65个有效的NIH赠款）。在这项建议中，我们开发和表征一种新的CMT小鼠模型，该模型携带在遗传形式的CMT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，其功能是沿着神经轴突运输货物。其他几种人类动力蛋白突变最近被证明会导致其他神经系统疾病，这表明对动力蛋白的研究在未来将变得非常重要。我们建议在基因敲入小鼠中表征人类动力蛋白疾病等位基因，以研究疾病发作和进展的机制。该提案的第一个目的是通过一系列行为测定来表征突变小鼠系中CMT疾病的发作和进展，这些行为测定检查了人类CMT表现的常见表型。在第二个目标中，我们将研究突变小鼠品系中动力蛋白的生物化学和生物物理特性。在第三个目标中，我们分析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表征和细胞转运测定相关联，我们希望对动力蛋白在神经系统疾病中的关键作用产生更全面的理解，最终导致更好的人类治疗，包括潜在的药物干预策略。