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）：肌萎缩性侧索硬化症（ALS）是运动神经元的致命神经退行性疾病，没有已知原因或有效治疗。我们对ALS发病机理的不良理解部分是由于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）博士学位提议使用强大的遗传有机体果蝇Melanogaster来表征和利用一种新型运动神经元疾病模型。新兴数据表明，轴突运输或其他囊泡运输事件的缺陷可能是该疾病的主要原因。为了研究囊泡转运在运动神经元疾病中的作用，我们在dynactin的P150亚基中引入了一种突变，以罕见的家族形式的ALS形式存在。表达突变体P150的苍蝇具有几种让人联想的ALS的表型，包括突变蛋白的聚集体，轴突转运中的缺陷以及成人发作，进行性麻痹和早期死亡。该提案的目的是进一步表征这种运动神经元疾病的简单遗传模型，然后使用它来筛选运动神经元变性的遗传抑制剂。 AIM 1将研究与疾病相关的P150突变对果蝇和体内果蝇中囊泡转运的影响，以检验这些突变破坏特定囊泡转运过程的假设。 AIM 2将检验以下假设：与疾病相关的P150突变导致运动神经元和神经肌肉连接病理类似于ALS患者。 AIM 3首先将表征突变体P150抑制器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的突变体P150的其他遗传修饰剂，以期识别对疾病发病机理至关重要的新基因，这是一种在小鼠模型中不可行的强大方法。鉴定出的遗传相互作用者是潜在的药物靶标，因此该建议的未来方向是验证ALS小鼠模型中已识别的相互作用基因。提出的研究将在果蝇和小鼠运动神经元连接的专家亚历克斯·科洛德金（Alex Kolodkin）实验室中进行，并由罗伯特·帕克德（Robert Packard）ALS研究中心主任杰夫·罗斯斯坦（Jeff Rothstein）进行指导。约翰·霍普金斯（Johns Hopkins）的神经科学和神经病学部门为发展神经科医生的发展提供了一个特殊的环境。这笔赠款提供的培训和指导将使劳埃德博士成为成功，独立的医师科学家所需的专业知识和工具，他们将他的职业生涯致力于确定对ALS的新疗法。相关性：由于缺乏该疾病的简单动物模型，阻碍了ALS治疗的发展。该提案将表征ALS的新果蝇模型，以帮助了解ALS的遗传原因，并帮助寻找这种毁灭性疾病的新药物目标。