Neurodegeneration and Proteotoxicity Dissected in C. elegans and Mammals

线虫和哺乳动物的神经变性和蛋白质毒性剖析

基本信息

批准号：
8237210
负责人：
Jiou Wang
金额：
$ 32.29万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-15 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8237210
关键词：
Aging Amyotrophic Lateral Sclerosis Attenuated Axon Caenorhabditis elegans Cell model Cells Cuprozinc Superoxide Dismutase Defect Disease Disease model Genes Genetic Screening Genetically Engineered Mouse Goals Human Invertebrates Laboratories Lead Link Lysine Mammalian Cell Mammals Mediating Modeling Molecular Molecular Genetics Mus Mutation Names Nematoda Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurons Orthologous Gene Pathogenesis Pathology Pathway interactions Phenotype Proteins Public Health Quality Control Regulatory Pathway Research Resources Role Societies Specificity Structure Synapses System Time Work age related base chemical genetics effective therapy genetic analysis innovation insight motor neuron degeneration mouse model mutant new therapeutic target novel novel strategies novel therapeutic intervention prevent protein TDP-43 protein aggregate protein aggregation protein degradation protein misfolding ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. In some forms of ALS, protein misfolding and aggregation of specific proteins, including Cu/Zn superoxide dismutase (SOD1), have been implicated in motor neuron degeneration. Considerable advances in the understanding of neurodegenerative diseases, including ALS, have been made through studies involving genetically engineered mouse models. However, the complexity, time, and resources required for analyzing age-dependent neurodegeneration in mice limit the usefulness of mouse systems for large-scale genetic and chemical screens. To overcome these limitations, this laboratory has developed and validated a simpler invertebrate model of ALS in Caenorhabditis elegans, a fast- growing, transparent nematode that is amenable to molecular genetic analysis. This C. elegans model recapitulates the major features of human ALS, including a pronounced locomotor defect and the protein aggregation pathology in neurons. This model has made it possible to dissect the mechanism of SOD1-induced neurodegeneration in an efficient manner, using unbiased and large-scale genetic screens. These studies have led to the identification of genes that influence and modulate the neurodegeneration and protein aggregation in ALS disease models. The goal of the proposed project is to identify and elucidate the mechanisms through which ALS pathogenesis is influenced by these novel modifiers. The specific aims are to identify and characterize key genes that influence and modulate the disease, to delineate the pathways through which the pathogenesis is influenced, and to extend the findings to related mammalian systems. The proposed studies, which combine mammalian systems with innovative and promising approaches using C. elegans, are expected to provide insight into fundamental mechanisms of neurodegeneration that may lead to novel approaches for treating ALS and related neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: The work in this proposal is aimed at elucidating the basic pathogenic mechanisms and the regulatory pathways involved in amyotrophic lateral sclerosis and related neurodegenerative diseases. Although these diseases are becoming an increasingly relevant public health challenge in our aging society, the mechanisms underlying most of these neurodegenerative conditions remain poorly understood. The molecular and genetic studies outlined in this proposal could lead to novel therapeutic interventions for those neurodegenerative diseases, including ALS, for which effective treatments are still lacking.

描述（由申请人提供）：肌萎缩性侧性硬化症（ALS）是一种进行性神经退行性疾病，其特征是运动神经元的退化。在某些形式的ALS中，包括Cu/Zn超氧化物歧化酶（SOD1）在内的特定蛋白质的蛋白质错误折叠和聚集已与运动神经元变性有关。通过涉及基因工程小鼠模型的研究，已经在了解包括ALS在内的神经退行性疾病的理解方面取得了长足的进步。但是，分析小鼠年龄依赖性神经变性所需的复杂性，时间和资源限制了小鼠系统对大规模遗传和化学筛查的有用性。为了克服这些局限性，该实验室已经开发并验证了Caenorhabditis elegrans中ALS的简单无脊椎动物模型，这是一种快速增长的透明线虫，可以适合分子遗传分析。秀丽隐杆线虫模型概括了人类ALS的主要特征，包括明显的运动缺陷和神经元中的蛋白质聚集病理学。该模型使使用无偏和大规模的遗传筛选以有效的方式以有效的方式剖析SOD1诱导的神经退行性的机制。这些研究导致了影响和调节ALS病模型中神经变性和蛋白质聚集的基因的鉴定。拟议项目的目的是识别和阐明ALS发病机理受这些新型修饰符影响的机制。具体的目的是识别和表征影响和调节疾病的关键基因，描述影响发病机理的途径，并将发现扩展到相关的哺乳动物系统。提出的研究将哺乳动物系统与秀丽隐杆线虫的创新和有前途的方法相结合，预计将洞悉神经变性的基本机制，这可能会导致治疗ALS和相关神经变性疾病的新方法。公共卫生相关性：该提案中的工作旨在阐明基本的致病机制以及肌萎缩性侧索硬化症和相关神经退行性疾病所涉及的调节途径。尽管这些疾病在我们老龄化社会中越来越相关的公共卫生挑战，但这些神经退行性疾病中大多数的机制仍然知之甚少。该提案中概述的分子和遗传研究可能会导致针对包括ALS在内的那些神经退行性疾病的新型治疗干预措施，这些疾病仍缺乏有效治疗。