Genetic Mechanisms of Motor Neuron Degeneration

运动神经元变性的遗传机制

• 批准号: 8031272
• 负责人: MICHAEL D KIM
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8031272
• 关键词: Alleles; Amyotrophic Lateral Sclerosis; Animal Model; Applications Grants; Axon; Behavior; Biological Assay; Cells; Cessation of life; Data; Development; Diagnosis; Disease; Drosophila genus; Etiology; Foundations; Functional disorder; Future; Gene Targeting; Genes; Genetic; Genetic Screening; Goals; Homologous Gene; Human; Inherited; Laboratories; Link; Locomotion; Modeling; Molecular; Motor; Motor Neurons; Mutation; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathology; Patients; Play; Population; Relative (related person); Research; Research Proposals; Resolution; Role; Stereotyping; Therapeutic; Therapeutic Human Experimentation; axonal degeneration; base; human disease; insight; late disease onset; loss of function; motor deficit; motor neuron degeneration; mutant; neuromuscular system; novel; overexpression; public health relevance

DESCRIPTION (provided by applicant): Genetic Mechanisms of Motor Neuron Degeneration Amyotrophic lateral sclerosis (ALS) is a fatal late-onset disease caused by the progressive degeneration of motor neurons. Although there has been considerable progress in the identification of genes linked to inherited cases of ALS, the etiology of this disease remains largely unknown. The lack of effective therapeutic treatments for patients diagnosed with ALS further underscores the importance of research directed at understanding the causes of this devastating disease. However, the identification of causative genes of ALS has been severely hindered by the lack of a simple laboratory model of motor neuron degeneration. The fruit fly Drosophila has played an instrumental role in our understanding of the pathogenesis of many human neurodegenerative diseases. The majority of Drosophila genes are highly conserved and, as a consequence, it is estimated that there is a homologous Drosophila gene for over 75% of human disease-causing genes. Furthermore, the relative simplicity of its neuromuscular system makes Drosophila an ideal model to study the genetic mechanisms underlying motor neuron degeneration. By creating genetic mosaics in Drosophila, our research allows us to visualize, with exquisite resolution, the phenotypic effects of deleterious mutations within a single motor neuron. This project will identify novel genes linked to motor neuron degeneration and determine the pathological basis of motor dysfunction in identified mutants using motor behavior assays. It is expected that this project will establish a novel Drosophila model of motor neuron degeneration that will significantly expand our current understanding of the etiology and pathogenesis of ALS and will further provide novel gene targets for future therapeutic research. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with no known cure. The proposed project will identify new genes linked to the progressive degeneration of motor neurons, significantly expanding our current understanding of the etiology and pathogenesis of ALS.

描述（由申请人提供）：运动神经元变性的遗传机制肌萎缩性侧索硬化症（ALS）是由运动神经元进行性变性引起的致命晚期疾病。尽管在与ALS遗传病例相关的基因的鉴定方面取得了很大进展，但该疾病的病因仍然很大程度上是未知的。缺乏对诊断患有ALS的患者的有效治疗方法进一步强调了针对理解这种毁灭性疾病的原因的研究的重要性。然而，由于缺乏简单的运动神经元变性模型，严重阻碍了ALS的病因基因的鉴定。果蝇果蝇在我们对许多人类神经退行性疾病的发病机理的理解中发挥了工具作用。大多数果蝇基因都是高度保守的，因此，据估计，有超过75％的致病基因有一个同源果蝇基因。此外，其神经肌肉系统的相对简单性使果蝇成为研究运动神经元变性的遗传机制的理想模型。通过在果蝇中创建遗传镶嵌物，我们的研究使我们能够通过精致的分辨率可视化，这是单个运动神经元内有害突变的表型效应。该项目将确定与运动神经元变性相关的新基因，并使用运动行为分析确定鉴定突变体中运动功能障碍的病理基础。预计该项目将建立一种新型的运动神经元变性的果蝇模型，该模型将大大扩展我们对ALS的病因和发病机理的当前理解，并将进一步为未来的治疗研究提供新颖的基因靶标。 公共卫生相关性：肌萎缩性侧索硬化症（ALS）是一种毁灭性的神经退行性疾病，没有已知的治愈方法。拟议的项目将确定与运动神经元进行性变性有关的新基因，从而显着扩展了我们当前对ALS病因和发病机理的理解。