Novel mechanisms of redox signaling in acute kidney injury

项目摘要 缺血再灌注或毒素诱导的急性肾损伤与线粒体损伤有关 功能障碍和ROS水平升高。ROS对DNA、蛋白质和脂质的破坏作用可 通过细胞抗氧化剂解毒ROS而得到改善。我发现了一种细胞凋亡的新机制 通过预测的假激酶硒蛋白O（SelO）在线粒体中解毒。初步研究 使用大肠coli和革兰氏阳性菌S.酿酒酵母证明，SelO催化AMP从ATP转移到多个 参与氧化还原稳态的底物，以抑制氧化损伤和防止细胞死亡。由于 从细菌到人类的种系传播和保存，我们假设SelO将在氧化应激中发挥作用 严重依赖线粒体的哺乳动物系统中的应激反应，如肾脏。我们 我将通过鉴定SelO介导的分子靶点和途径，并通过分析SelO的生物学特性，来验证这一假说。 SelO在啮齿类顺铂诱导的急性肾损伤模型中的功能重要性。深 在氧化应激和肾病学领域的理解和技术专长是至关重要的 成功完成此提案。这个职业发展奖将使我能够加强我的科学 在肾脏分离、染色和表型表征方面的培训，结合生化 用于评估线粒体健康的分析。这些研究将为神经系统的信号转导提供一个新的范式。 线粒体，它可以被篡夺，以确定治疗靶点，以防止氧化损伤的过多 包括急性肾损伤的病理学。

PROJECT SUMMARY Acute kidney injury resulting from ischemia reperfusion or toxin induced damage is correlated with mitochondrial dysfunction and increased ROS levels. The damaging effects of ROS on DNA, protein and lipids can be ameliorated by cellular antioxidants that detoxify the ROS. I have identified a novel mechanism of cellular detoxification in the mitochondria by a predicted pseudokinase, Selenoprotein O (SelO). Preliminary studies using E. coli and S. cerevisiae demonstrates that SelO catalyzes the transfer of AMP from ATP to multiple substrates involved in redox homeostasis to dampen oxidative damage and prevent cell death. Due to the phyletic spread and conservation from bacteria to humans, we postulate that SelO will play a role in oxidative stress response in mammalian systems that are heavily dependent on the mitochondria, such as the kidney. We will test this hypothesis by identifying the molecular targets and pathways mediated by SelO, and characterizing the functional importance of SelO in the rodent cisplatin-induced acute kidney injury model. A deep understanding and technical expertise in the fields of oxidative stress and nephrology are essential to the successful completion of this proposal. This career development award will allow me to strengthen my scientific skill set by training in kidney isolation, staining and phenotypic characterization in combination with biochemical assays to evaluate mitochondrial health. These studies will define a novel paradigm of signaling in the mitochondria, which can be usurped to identify therapeutic targets to prevent oxidative damage in a plethora of pathologies including acute kidney injury.