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

使用 P150 / Dynactin 突变的果蝇运动神经元疾病模型。

基本信息

批准号：
8079726
负责人：
Thomas E. Lloyd
金额：
$ 17.56万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8079726
关键词：
Adult Age Alleles Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animal Disease Models Animal Model Animals Apoptotic Autophagocytosis Axon Axonal Transport Biological Assay Cell Death Cells Cessation of life Clinical Trials Data Defect Development Disease Doctor of Medicine Doctor of Philosophy Dominant-Negative Mutation Drosophila genome Drosophila genus Drosophila melanogaster Drug Delivery Systems Endosomes Environment Event Exhibits Eye Familial Motor Neuron Disease Functional disorder Future Genes Genetic Genetic Models Genetic Screening Genome Glycine Goals Golgi Apparatus Grant Histology Human Huntington Disease Impairment In Vitro Inherited Kinesin Laboratories Lower Motor Neuron Disease Lysosomes Mentorship Microtubules Modeling Motor Motor Neuron Disease Motor Neurons Mus Mutate Mutation Nerve Degeneration Neurodegenerative Disorders Neurologist Neurology Neuromuscular Junction Neurons Neurosciences Organelles Organism Paralysed Parkinson Disease Pathogenesis Pathologic Pathology Patients Phenotype Physicians Proteins Research Research Personnel Research Proposals Role Scientist Signal Transduction Synapses System Techniques Testing Training Transgenic Mice Transport Process Transport Vesicles Vesicle Vesicle Transport Pathway Wing anterograde transport career disease phenotype dynactin effective therapy fly human disease in vivo insight loss of function mature animal motor neuron degeneration mouse model mutant neuromuscular neuron loss novel overexpression protein complex synaptogenesis therapy development tool trafficking tyrosine kinase ABL1 young adult

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：肌萎缩侧索硬化症（ALS）是一种致命的运动神经元神经退行性疾病，病因不明，也没有有效的治疗方法。我们对 ALS 发病机制了解甚少，部分原因是缺乏运动神经元变性的简单动物模型。候选人托马斯·劳埃德 (Thomas Lloyd) 医学博士、哲学博士提出利用强大的遗传生物果蝇来表征和利用运动神经元疾病的新模型。新数据表明轴突运输或其他囊泡运输事件的缺陷可能是这种疾病的主要原因。为了研究囊泡转运在运动神经元疾病中的作用，我们将 dynactin P150 亚基的突变引入果蝇中，这种突变存在于一种罕见的家族性 ALS 中。表达突变 P150 的果蝇具有多种让人想起 ALS 的表型，包括突变蛋白聚集、轴突运输缺陷以及成年发病、进行性瘫痪和早期死亡。该提案的目标是进一步表征运动神经元疾病的这种简单遗传模型，然后用它来筛选运动神经元变性的遗传抑制因子。目标 1 将研究疾病相关的 P150 突变对果蝇体外和体内囊泡转运的影响，以检验这些突变破坏特定囊泡转运过程的假设。目标 2 将检验以下假设：与疾病相关的 P150 突变会导致运动神经元和神经肌肉接头病理学类似于 ALS 患者中所见的病理学。目标 3 将首先表征已确定的突变 P150 抑制因子对这些运动神经元表型的影响。然后，我们将筛选果蝇基因组中突变 P150 的其他遗传修饰剂，希望能够识别出对疾病发病机制至关重要的新基因，这是一种在小鼠模型中不可行的强大方法。已识别的基因相互作用因子是潜在的药物靶标，因此该提案的未来方向是在 ALS 小鼠模型中验证已识别的相互作用基因。拟议的研究将在果蝇和小鼠运动神经元连接方面的专家 Alex Kolodkin 的实验室中进行，并得到 Robert Packard ALS 研究中心主任 Jeff Rothstein 的指导。约翰·霍普金斯大学的神经科学和神经病学系为学术神经学家的发展提供了优越的环境。这笔赠款提供的培训和指导将为 Lloyd 博士提供成为一名成功的独立医师科学家所需的专业知识和工具，他将致力于寻找 ALS 的新疗法。相关性：ALS 治疗方法的开发因缺乏该疾病的简单动物模型而受到阻碍。该提案将描述一种新的 ALS 果蝇模型，以帮助了解 ALS 的遗传原因，并帮助寻找针对这种毁灭性疾病的新药物靶点。