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。

• 批准号: 8268467
• 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
• 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/8268467
• 关键词: Adult; Age; Alleles; Alzheimer' 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

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.

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，其病因尚不清楚。 原因或有效治疗。我们对 ALS 发病机制了解甚少，部分原因是缺乏简单的方法 运动神经元变性的动物模型。候选人托马斯·劳埃德 (Thomas Lloyd) 医学博士、哲学博士提议 利用强大的遗传有机体表征和利用运动神经元疾病的新模型 黑腹果蝇。新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。研究囊泡运输在运动神经元中的作用 疾病，我们已将 dynactin 的 P150 亚基的突变引入果蝇中，该突变存在于 罕见的家族性 ALS。表达突变体 P150 的果蝇有几种让人想起 ALS 的表型 包括突变蛋白的聚集、轴突运输缺陷以及成人发病的进行性瘫痪 和早逝。该提案的目标是进一步表征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基因。目标1 将在体外研究疾病相关的 P150 突变对果蝇囊泡运输的影响 并在体内测试这些突变破坏特定囊泡运输过程的假设。目标2将 检验疾病相关 P150 突变导致运动神经元和神经肌肉接头的假设 病理学与 ALS 患者相似。目标 3 将首先描述已确定的影响 这些运动神经元表型上突变 P150 的抑制因子。然后我们将筛选果蝇基因组 对突变体 P150 进行额外的遗传修饰，以期鉴定出对疾病至关重要的新基因 发病机制，这是一种在小鼠模型中不可行的强大方法。已确定的遗传相互作用因素是潜在的 药物靶点，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 肌萎缩侧索硬化症。拟议的研究将在电机专家 Alex Kolodkin 的实验室进行 在罗伯特研究所所长 Jeff Rothstein 的指导下，果蝇和小鼠的神经元连接 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特殊的环境。培训和指导 这笔赠款所提供的资金将为劳埃德博士提供成为成功的、 独立医师兼科学家，将致力于寻找 ALS 的新疗法。 相关性：由于缺乏简单的动物模型，ALS 治疗方法的发展受到阻碍。 这种病。该提案将描述一种新的 ALS 果蝇模型，以帮助理解 ALS 的遗传机制。 ALS 的病因并帮助寻找针对这种毁灭性疾病的新药物靶标。

项目成果

Novel therapeutic approaches for inclusion body myositis.

包涵体肌炎的新治疗方法。

• DOI: 10.1097/bor.0b013e32833f0f4a
• 发表时间: 2010
• 期刊: Current opinion in rheumatology
• 影响因子: 5.1
• 作者: Lloyd,ThomasE

Peripheral neuropathy: clinical and electrophysiological considerations.

• DOI: 10.1016/j.nic.2013.03.023
• 发表时间: 2014-02
• 期刊: Neuroimaging clinics of North America
• 影响因子: 2.3
• 作者: Chung T;Prasad K;Lloyd TE
• 通讯作者: Lloyd TE

Flightless flies: Drosophila models of neuromuscular disease.

• DOI: 10.1111/j.1749-6632.2010.05432.x
• 发表时间: 2010-01
• 期刊: Annals of the New York Academy of Sciences
• 影响因子: 5.2
• 作者: Lloyd TE;Taylor JP
• 通讯作者: Taylor JP

Axonal transport disruption in peripheral nerve disease: From Jack's discoveries as a resident to recent contributions.

• DOI: 10.1111/j.1529-8027.2012.00431.x
• 发表时间: 2012-12
• 期刊: Journal of the peripheral nervous system : JPNS
• 作者: Lloyd TE