Molecular Mechanism of Toxin-Induced Protein Misfolding

描述（由申请方提供）：已发现小分子毒素与许多蛋白质错误折叠疾病流行病学相关。使用亚砷酸盐（As（III））作为一个模型系统，改变全球蛋白质折叠在体内的环境毒素的潜在作用进行了分析。As（III）诱导的蛋白质错误折叠的机制将通过比较发现在As（III）处理的细胞中错误折叠的蛋白质和发现原位结合As（III）的蛋白质来评估。As（III）诱导的错误折叠将通过比较As（III）处理的细胞中的错误折叠蛋白质和用其它应激诱导剂处理的细胞中的错误折叠蛋白质来进一步表征，从而阐明As（III）诱导的错误折叠的机制。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）毒性中的作用。这项工作不仅将确定潜在的治疗目标，为众多的人群易患人类疾病的As（III）曝光，但它也将允许更好地了解环境毒素的作用，在易患人群蛋白质错误折叠疾病的老化和神经变性。

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.