A Drosophila model of motor neuron disease using mutations in P150 / Dynactin.

肌萎缩侧索硬化症（ALS）是一种致命的运动神经元退行性疾病， 病因或有效治疗。我们对ALS发病机制的认识不足，部分原因是缺乏简单的 运动神经元变性的动物模型。候选人医学博士托马斯·劳埃德博士建议 利用强大的遗传生物体表征和利用运动神经元疾病的新模型， 果蝇新的数据表明，轴突运输或其他囊泡运输的缺陷， 事件可能是这种疾病的主要原因。探讨囊泡转运在运动神经元中的作用 疾病，我们已经引入了一个突变的P150亚基的dynactin到果蝇，这是目前在一个 罕见的家族性肌萎缩侧索硬化症表达突变型P150的果蝇具有几种ALS的表型 包括突变蛋白的聚集、轴突运输缺陷和成人发病的进行性麻痹 早死。这项提议的目的是进一步描述这种简单的运动遗传模型， 神经元疾病，然后用它来筛选运动神经元变性的遗传抑制因子。要求1 将研究疾病相关的P150突变对果蝇体外囊泡转运的影响 并在体内测试这些突变破坏特定囊泡转运过程的假设。目标2将 检验疾病相关的P150突变导致运动神经元和神经肌肉接头的假设 类似于ALS患者中所见的病理学。目标3将首先描述已确定的 突变P150对这些运动神经元表型的抑制作用。然后我们将筛选果蝇的基因组 寻找突变型P150的其他遗传修饰剂，希望能找到对疾病至关重要的新基因。 发病机制，一个强大的方法在小鼠模型中不可行。确定的遗传相互作用是潜在的 因此，该提案的未来方向是在小鼠模型中验证已识别的相互作用基因 的ALS。这项研究将在汽车专家Alex Kolodkin的实验室进行。 果蝇和小鼠的神经元连接，由罗伯特·罗斯坦（Robert Rothstein）主任杰夫·罗斯坦（Jeff Rothstein）指导 帕卡德ALS研究中心。约翰霍普金斯大学的神经科学和神经病学部门提供 为学术神经学家的发展提供了一个特殊的环境。培训和指导 这笔赠款提供的将给劳埃德博士的专业知识和工具，成为一个成功的， 他是一位独立的医生兼科学家，将致力于为ALS寻找新的治疗方法。 相关性：ALS治疗的发展受到缺乏简单的动物模型的阻碍。 这种疾病。该提案将描述ALS的新果蝇模型，以帮助了解ALS的遗传特性。 并帮助寻找针对这种毁灭性疾病的新药靶标。

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease of motor neurons without a known cause or effective treatment. Our poor understanding of ALS pathogenesis is partly due to a lack of simple animal models of motor neuron degeneration. The candidate, Thomas Lloyd M.D., Ph.D. proposes to characterize and utilize a novel model of motor neuron disease using the powerful genetic organism Drosophila melanogaster. Emerging data suggest that defects in axonal transport or other vesicle trafficking events may be a primary cause of this disease. To investigate the role of vesicle transport in motor neuron disease, we have introduced a mutation in the P150 subunit of dynactin into Drosophila that is present in a rare familial form of ALS. Flies expressing mutant P150 have several phenotypes reminiscent of ALS including aggregates of mutant protein, defects in axonal transport, and adult-onset, progressive paralysis and early death. The goal of this proposal is to further characterize this simple genetic model of motor neuron disease, and then to use it to screen for genetic suppressors of motor neuron degeneration. Aim 1 will investigate the effects of disease-associated P150 mutations on vesicle transport in Drosophila in vitro and in vivo to test the hypothesis that these mutations disrupt specific vesicle transport processes. Aim 2 will test the hypothesis that disease-associated P150 mutations cause motor neuron and neuromuscular junction pathology resembling that seen in ALS patients. Aim 3 will first characterize the effect of an identified suppressor of mutant P150 on these motor neuron phenotypes. We will then screen the Drosophila genome for additional genetic modifiers of mutant P150 in hopes of identifying novel genes critical to disease pathogenesis, a powerful approach not feasible in mouse models. Identified genetic interactors are potential drug targets, so a future direction of this proposal is to validate identified interacting genes in mouse models of ALS. The studies proposed will be carried out in the laboratory of Alex Kolodkin, an expert in motor neuron connectivity in Drosophila and mice, with mentorship from Jeff Rothstein, director of the Robert Packard Center for ALS Research. The neuroscience and neurology departments at Johns Hopkins provide an exceptional environment for the development of academic neurologists. The training and mentorship provided by this grant will give Dr. Lloyd the expertise and tools needed to become a successful, independent physician-scientist who will devote his career to identifying new treatments for ALS. RELEVANCE: The development of treatments for ALS is hindered by the lack of simple animal models of this disease. This proposal will characterize a new fruitfly model of ALS to help understand the genetic causes of ALS and to help find new drugs targets for this devastating disease.