O2 SENSING BY MITOCHONDRIA DURING INTERMITTENT HYPOXIA

阻塞性睡眠呼吸暂停（OSA）是一种临床综合征，其特征是反复发作， 间歇性关闭上呼吸道引起的严重低氧血症发作 睡眠时的呼吸道OSA的并发症包括肺动脉高压 是由肺血管重塑引起的 反复间歇性缺氧是 最有可能的原因 缺氧后的重构反应 这意味着存在一种细胞O2传感器 [O2]的变化。 这个实验室的研究表明线粒体 在不同的细胞中作为氧传感器，在缺氧期间释放反应性 氧物种（ROS）的细胞质，触发细胞内信号 导致转录因子核因子激活的途径 NF κ B（NF κ B）和缺氧诱导因子（HIF- 1）， 调节其他人的适应性代谢反应。 本申请提出 线粒体在间歇性缺氧期间也起着O2传感器的作用， 释放导致转录因子NF κ B活化的ROS， HIF-I和AP-I调节参与长期血管生成的基因， 重塑 生长因子有助于细胞增殖， 缺氧通过一种未知的方式放大了它们的促有丝分裂反应。 机制 缺氧时释放的线粒体ROS可以放大线粒体内的 通过增强氧化剂信号传导对生长因子的促有丝分裂反应 这是它们增殖反应所必需的。我将决定是否 线粒体作为O2传感器，在间歇性的 缺氧 目标2将确定这些ROS是否是必要和充分的 用于激活转录因子NF κ B、HIF-1和AP- 1，和 这些因子是否介导随后的转录激活， 靶基因参与血管重塑。 目标3将决定是否 间歇性缺氧通过以下方式增强对有丝分裂原的增殖反应： 刺激线粒体ROS生成，增强生长因子诱导的 非线粒体氧化剂信号传导。 总的来说，这些研究可以 确定肺中O2感知的新机制，并提供 基因转录激活的机制解释和细胞 在间歇性缺氧期间增殖。

Obstructive sleep apnea (OSA) is a clinical syndrome characterized by repeated episodes of severe hypoxemia caused by intermittent closure of the upper airway during sleep. Complications of OSA include pulmonary hypertension caused by vascular remodeling in the lung. Repeated intermittent hypoxia is the most likely cause of this remodeling. The remodeling responses to hypoxia imply that a cellular O2 sensor exists that is capable of responding to rapid changes in [O2]. Studies from this laboratory indicate that mitochondria function as O2 sensors during hypoxia in diverse cells, releasing reactive oxygen species (ROS) to the cytoplasm that trigger intracellular signaling pathways leading to the activation of the transcription factors Nuclear Factor kappa B (NFkB) and Hypoxia-Inducible Factor (HIF- 1) in some cells, and that mediate adaptive metabolic responses in others. This application proposes that mitochondria also function as O2 sensors during intermittent hypoxia, by releasing ROS that lead to the activation of the transcription factors NFkB, HIF- I and AP- I that regulate genes involved in long-term vascular remodeling. Growth factors contribute to proliferation of cells in the vascular wall, and hypoxia amplifies their mitogenic response via an unknown mechanism. Mitochondrial ROS released during hypoxia could amplify the mitogenic response to growth factors by augmenting the oxidant signaling required for their proliferative response. Aim I will determine whether mitochondria function as O2 sensors by releasing ROS during intermittent hypoxia. Aim 2 will determine whether these ROS are necessary and sufficient for the activation of the transcription factors NFkB, HIF- I and AP- 1, and whether these factors mediate the subsequent transcriptional activation of target genes involved in vascular remodeling. Aim 3 will determine whether intermittent hypoxia amplifies the proliferative response to mitogens by stimulating mitochondrial ROS generation that augments growth factor-induced non-mitochondrial oxidant signaling. Collectively, these studies could identify a novel mechanism of O2 sensing in the lung, and provide a mechanistic explanation for the activation of gene transcritpion and cellular proliferation during intermittent hypoxia.