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

• 批准号: 9281039
• 负责人: Jiou Wang
• 金额: $ 45.62万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9281039
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Behavioral; Biochemical Genetics; Biological; Caenorhabditis elegans; Cells; Creutzfeldt-Jakob Syndrome; Defense Mechanisms; Disease; Early identification; Frontotemporal Dementia; Future; Genes; Genetic; Genetic Screening; Genetic study; Hand; Heat-Shock Response; Huntington Disease; Invertebrates; Investigation; L3MBTL1 gene; Lead; Link; Mammalian Cell; Mammals; Mathematics; Mediating; Modeling; Molecular; Molecular Genetics; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenicity; Pathologic; Pathway interactions; Patients; Phenotype; Protein p53; Proteins; Public Health; Quality Control; Regulation; Regulatory Pathway; Research; Role; Societies; Stress; Suppressor Genes; System; TP53 gene; Therapeutic Intervention; Toxic effect; Work; aging population; base; effective therapy; in vivo; insight; interest; member; misfolded protein; motor neuron degeneration; mouse model; novel; novel therapeutic intervention; prevent; protein TDP-43; protein aggregation; protein misfolding; proteostasis; proteotoxicity; response; screening; stressor; success; superoxide dismutase 1; transcription factor

Project Summary Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of motor neurons. Protein misfolding and aggregation are a central feature of ALS and related neurodegenerative diseases. The complexity of neurodegeneration calls for large-scale unbiased screening studies. Over the past few years, we have made breakthrough observations that have significant implications for the understanding of cellular defense systems against proteotoxicity. Using a unique blend of biochemical, genetic, and cell biological approaches, we discovered a novel pathway to reprogram protein quality control, and with new genetic hits related to this pathway in hand. We now propose work to elucidate a previously unrecognized p53 network in protein quality control. The studies on this network could expand our understanding of proteotoxic-stress-responsive quality control systems in the cell, beyond the well-established heat shock response or unfolded protein response. Our unique potential to contribute to this field is both technical and conceptual: We have developed a unique tandem C. elegans/mammalian system to study neurodegeneration, and our recent success bodes well for future plans. For example, our expanding repertoire of diease models will allow us to conduct unbiased screening studies of proteotoxicity-associated neurodegeneration in vivo and extend the findings to mammalian models and patient cells. The findings will not only provide novel entry points for understanding the molecular causes of key ALS genes but also suggest new strategies for harnessing the cellular defense system to prevent and treat the relevant forms of ALS and other related neurodegenerative diseases. We predict that the advances gained through our research efforts will eventually lead to new therapeutic interventions to address these diseases in the world's rapidly aging population.

项目概要 肌萎缩侧索硬化症 (ALS) 是一种进行性神经退行性疾病 以运动神经元退化为特征。蛋白质错误折叠和聚集是 ALS 和相关神经退行性疾病的核心特征。复杂度 神经退行性疾病需要大规模公正的筛查研究。在过去的几年里， 我们取得了突破性的观察结果，对 了解针对蛋白质毒性的细胞防御系统。使用独特的混合物 通过生物化学、遗传和细胞生物学方法，我们发现了一条新的途径 重新编程蛋白质质量控​​制，并掌握与该途径相关的新基因命中。我们 现在提出工作来阐明蛋白质质量控​​制中以前未被识别的 p53 网络。 对该网络的研究可以扩大我们对蛋白毒性应激反应的理解 细胞内的质量控制系统，超出了既定的热休克反应或展开 蛋白质反应。我们为这一领域做出贡献的独特潜力既体现在技术上，也体现在 概念：我们开发了一种独特的串联线虫/哺乳动物系统来研究 神经退行性疾病，我们最近的成功预示着未来的计划。例如，我们的 扩大疾病模型库将使我们能够进行公正的筛选研究 体内蛋白质毒性相关的神经变性并将研究结果扩展到哺乳动物 模型和患者细胞。研究结果不仅为理解提供了新的切入点 关键 ALS 基因的分子原因，同时也提出了利用该基因的新策略 细胞防御系统，用于预防和治疗相关形式的 ALS 和其他相关疾病 神经退行性疾病。我们预测通过我们的研究工作所取得的进步 最终将导致新的治疗干预措施来解决世界范围内的这些疾病 人口迅速老龄化。