Genetic Determinants of Hyperoxia Stress

这项建议的总体目标是了解细胞中高氧敏感性的遗传决定因素。 高氧，或暴露于高于正常的氧气浓度，是一个重要的健康问题，因为它可以导致严重的肺相关损伤。据推测，高氧的毒性涉及活性氧的产生;然而，关于影响这种损害的因素知之甚少。 使用酿酒酵母作为模型系统，将识别和表征保护免受高氧损伤的基因。 酵母缺失突变体的完整文库的遗传筛选已经启动，鉴定对高氧敏感的突变体。初步结果表明，对高氧的保护涉及一组抗氧化因子，这是独特的这种类型的氧化应激。在未来的研究中，这一遗传筛查将完成（目标1），我们将开始解决高氧损伤的潜在机制（目标2）。 将测试突变体对其他氧化剂的敏感性，并探讨金属在高氧毒性中的潜在作用。 已经选择了一种特定的高氧突变体用于详细分析：pos 5（Aim 3）。P0 S5编码基于同源性的未表征的蛋白质，其可影响细胞表面铁还原酶活性。 铁还原酶，铁和POS 5之间的可能联系，防止高氧中毒将进行探讨。

The overall goal of this proposal is to understand the genetic determinants of hyperoxia sensitivity in the cell. Hyperoxia, or exposure to higher than normal oxygen concentrations, is an important health problem since it can lead to serious lung-related injury. Presumably, toxicity from hyperoxia involves the production of reactive oxygen species; however, very little is known regarding the factors that influence this damage. Using Saccharomyces cerevisiae as a model system, genes that protect against hyperoxia damage will be identified and characterized. A genetic screen of the complete library of yeast deletion mutants has been initiated, identifying mutants that are sensitive to hyperoxia. Initial results indicate that protection against hyperoxia involves a set of antioxidant factors that is distinct for this type of oxidative stress. In future studies, this genetic screen will be completed (Aim 1), and we will begin to address the mechanisms underlying hyperoxia damage (Aim 2). The mutants will be tested for sensitivity to other oxidants and a potential role for metals in hyperoxia toxicity will be explored. One particular hyperoxia mutant has been selected for analysis in detail: pos5 (Aim 3). POS5 encodes an uncharacterized protein, that based on homology, may influence cell surface ferrireductase activity. The possible connection between ferrireductase, iron and POS5 in guarding against toxicity from hyperoxia will be explored.