Mitochondria-Derived Reactive Oxygen Species and Nox4 in Pulmonary Hypertension

描述（由申请人提供）：肺动脉高压（PH）的特征是肺血管阻力增加、肺血管重塑和血压升高，通常导致右心室肥大。这些血管变化最终可导致右心衰竭。目前的证据表明，线粒体呼吸和NADPH氧化酶活性产生的活性氧（ROS）可能在血管细胞增殖，右心室肥大和PH发病机制中发挥作用。本研究探讨了在缺氧诱导的PH的发展中，由NADPH氧化酶活性产生的ROS和由NADPH衍生的ROS之间的串扰的作用。NADPH氧化酶（Noxes）与细胞ROS的产生有关，据信通过增加增殖促进PH的发病机制。一些研究还暗示线粒体ROS有助于细胞内氧化还原平衡失调介导的内皮细胞功能障碍。尽管PH发生/进展的潜在机制仍不完全确定，但我们假设缺氧暴露增加了ROS的产生，这是线粒体产生的ROS与对肺血管细胞具有不同作用的Nox之间的串扰的结果。这些ROS隔室通过差异影响NADPH氧化酶、增殖基因和凋亡信号传导标记物的表达来影响缺氧诱导的增殖，从而差异调节血管重塑和可能的肺动脉高压。我们相信，NADPH氧化酶家族成员的表达或活性的调节将提供一种新的机制，以特异性靶向ROS的产生，防止内皮功能障碍和防止肺动脉高压。因此，该提议涉及两个具体目的：1）探索ROS源之间的串扰在内皮增殖、ROS产生和凋亡的缺氧诱导的改变中的作用（目的1），和2）确定在缺氧诱导的肺动脉高压新型鼠模型中，源自ESTA的ROS和Nox 4之间的串扰的作用（目的2）。这些目标将在Roy L.博士的指导下通过分子和药理学实验来实现。Sutliff和Dr. C.迈克尔哈特。这些结果旨在明确解决导致和帮助PH病理的分子机制。这个NRSA赠款资金，沿着的援助，从我建立的导师，并在埃默里大学提供的几个培训机会，这个博士前的培训将用于扩大我的研究技术，实验设计和手稿写作的知识。这个奖项将为我成为一名独立的学术研究人员的长期目标做好准备。

DESCRIPTION (provided by applicant): Pulmonary Hypertension (PH) is characterized by increased pulmonary vascular resistance, pulmonary vascular remodeling, and increases in blood pressure that often results in right ventricular hypertrophy. These vascular changes can ultimately result in right heart failure. Current evidence suggests that reactive oxygen species (ROS) generated by both mitochondrial respiration and NADPH oxidase activity may play a role in vascular cell proliferation, right ventricular hypertrophy, and PH pathogenesis. The present study examines the role of crosstalk between mitochondria-derived ROS and ROS generated via NADPH oxidase activity in the development of hypoxia-induced PH. NADPH Oxidases (Noxes) are implicated in the generation of cellular ROS generation in the believed to promote PH pathogenesis by increasing proliferation. Some studies have also implicated mitochondrial ROS as contributing to endothelial cell dysfunction mediated by disregulated redox balance within the cell. Though the mechanism(s) underlying the development/progression of PH remain incompletely defined, we hypothesize that hypoxia exposure increases ROS generation and this occurs as the result of crosstalk between ROS generated by the mitochondria and Noxes which have deferential effects on the cells of the pulmonary vasculature. These ROS compartments impact hypoxia-induced proliferation by differentially affecting expression of NADPH oxidase, proliferation genes, and apoptotic signaling markers and thereby differentially regulate vascular remodeling and possibly pulmonary hypertension. We believe that modulation of the expression or activity of NADPH oxidase family members will provide a novel mechanism to specifically target ROS generation, preventing endothelial dysfunction and preventing pulmonary hypertension. This proposal therefore involves two specific aims: 1) To explore the role of crosstalk between ROS sources in hypoxia-induced alterations in endothelial proliferation, ROS generation, and apoptosis (Aim 1), and 2) to determine the role of crosstalk between mitochondria-derived ROS and Nox4 in hypoxia-induced pulmonary hypertension novel murine models (Aim 2). These aims will be accomplished through both molecular and pharmacological experimentation under the guidance of Dr. Roy L. Sutliff and Dr. C. Michael Hart. These results aim to clearly address the molecular mechanism leading to and aiding PH pathology. This NRSA grant funding, along with assistance from my established mentors, and the several training opportunities available at Emory University, this pre-doctoral training will be used to expand my knowledge of research techniques, experimental design, and manuscript writing. This award will prepare me for my long-term goal of becoming an independent academic researcher.