Molecular Mechanism of Toxin-Induced Protein Misfolding

毒素诱导蛋白质错误折叠的分子机制

• 批准号: 7112103
• 负责人: Rockland Luke Wiseman
• 金额: $ 4.4万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7112103
• 关键词: SDS polyacrylamide gel electrophoresis; arsenic; binding proteins; biophysics; cytoplasm; cytoprotection; cytotoxicity; diabetes mellitus; environment related neoplasm /cancer; environmental toxicology; intermolecular interaction; matrix assisted laser desorption ionization; molecular chaperones; molecular pathology; nervous system disorder; neural degeneration; postdoctoral investigator; protein folding; protein structure function; radiotracer; small molecule; teratogens; toxin

DESCRIPTION (provided by applicant): Small molecule toxins have been found to be epidemiologically linked to a number of protein misfolding diseases. Using arsenite (As(lll)) as a model system, the potential role of environmental toxins on altering the global protein fold in vivo will be analyzed. The mechanism of As(lll)-induced protein misfolding will be evaluated by comparing the proteins found to be misfolded in As(lll)-treated cells and proteins that are found to bind As(lll) in situ. As(lll)-induced misfolding will be further characterized by comparisons between the misfolded proteins in As(lll) treated cells and misfolded proteins in cells treated with other stress- inducing agents, allowing the mechanism of As(lll)-induced misfolding to be elucidated. Using the methods outlined in this proposal, the role of the Integrated Stress Response and AIRAP in protecting cells against As(lll) toxicity will be also be examined. This work will not only identify potential therapeutic targets for the numerous human populations predisposed to human disease by As(lll) exposure, but it will also allow for a better understanding of the role environmental toxins play in predisposing populations to protein misfolding diseases of aging and neurodegeneration.

描述（由申请人提供）：已发现小分子毒素在流行病学上与许多蛋白质错误折叠疾病有关。使用亚砷酸盐（As(III)）作为模型系统，将分析环境毒素对改变体内整体蛋白质折叠的潜在作用。 As(III)诱导的蛋白质错误折叠的机制将通过比较在As(III)处理的细胞中发现错误折叠的蛋白质和发现原位结合As(III)的蛋白质来评估。通过比较 As(III) 处理的细胞中的错误折叠蛋白和用其他应激诱导剂处理的细胞中的错误折叠蛋白，将进一步表征 As(III) 诱导的错误折叠，从而使 As(III) 诱导的错误折叠机制得以阐明。阐明了。使用本提案中概述的方法，还将检查综合应激反应和 AIRAP 在保护细胞免受 As(III) 毒性方面的作用。这项工作不仅可以为众多因接触 As(III) 而易患人类疾病的人群确定潜在的治疗靶点，而且还可以更好地了解环境毒素在易患衰老和蛋白质错误折叠疾病的人群中所起的作用。神经变性。