Mitochondria-Derived Reactive Oxygen Species and Nox4 in Pulmonary Hypertension

线粒体衍生的活性氧和 Nox4 在肺动脉高压中的作用

• 批准号: 8459698
• 负责人: Sherry Adesina
• 金额: $ 3.09万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2015-09-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8459698
• 关键词: Address; Affect; Animals; Antimycin A; Antioxidants; Apoptosis; Apoptotic; Attenuated; Award; Biological Assay; Blood Pressure; Blood Vessels; Caspase; Cell Count; Cell Hypoxia; Cell Proliferation; Cell Wall; Cells; Cessation of life; Complex; Development; Disease; Electron Transport Complex III; Endothelial Cells; Equilibrium; Experimental Designs; Family member; Fluorescent Probes; Functional disorder; Funding; Generations; Genes; Goals; Grant; Heart failure; Hour; Human; Hydrogen Peroxide; Hypoxia; Immunohistochemistry; In Vitro; Knowledge; Lung; Manuscripts; Measurement; Measures; Mediating; Mentors; Messenger RNA; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mus; NADPH Oxidase; National Research Service Awards; Oxidation-Reduction; Oxidative Phosphorylation; Pathogenesis; Pathology; Play; Poly(ADP-ribose) Polymerases; Proteins; Protocols documentation; Pulmonary Hypertension; Pulmonary Vascular Resistance; Reactive Oxygen Species; Reporting; Research Personnel; Research Technics; Respiration; Right Ventricular Hypertrophy; Role; Rotenone; SOD2 gene; Signal Pathway; Signal Transduction; Smooth Muscle; Smooth Muscle Myocytes; Source; Staining method; Stains; Stimulus; Superoxide Dismutase; Superoxides; Symptoms; Systolic Pressure; Tissues; Training; Transgenic Mice; Transgenic Organisms; Universities; Vascular Smooth Muscle; Vascular remodeling; Ventricular; Weight; Western Blotting; Writing; catalase; human subject; in vivo; mortality; mouse model; novel; overexpression; pre-doctoral; pressure; prevent; public health relevance; pulmonary arterial hypertension; pulmonary artery endothelial cell; response; skills; superoxide-generating NADPH oxidase

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.

描述(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，血压升高，通常导致右室肥厚。这些血管变化最终会导致右心衰竭。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物种(ROS)可能在血管细胞增殖、右室肥厚和PH的发病机制中发挥作用。本研究探讨了线粒体来源的ROS和通过NADPH氧化酶活性产生的ROS之间的串扰在低氧诱导的PH发生中的作用。NADPH氧化酶(NOX)参与了细胞内ROS的产生，被认为通过促进增殖促进了PH的发病。一些研究还表明，线粒体ROS参与了细胞内氧化还原平衡失调所介导的内皮细胞功能障碍。尽管肺高压发生发展的机制(S)仍不完全清楚，但我们推测，低氧暴露增加了ROS的产生，这是线粒体产生的ROS与对肺血管细胞有不同作用的NOX之间相互作用的结果。这些ROS通过不同地影响NADPH氧化酶、增殖基因和凋亡信号标记物的表达来影响低氧诱导的增殖，从而不同地调节血管重构和可能的肺动脉高压。我们认为，调控NADPH氧化酶家族成员的表达或活性将为特异性靶向ROS的产生、预防内皮功能障碍和预防肺动脉高压提供新的机制。因此，该建议涉及两个特定的目标：1)探讨ROS来源之间的串扰在缺氧诱导的内皮细胞增殖、ROS生成和细胞凋亡中的作用(目标1)；2)确定线粒体来源的ROS和NOX4之间的串扰在新的缺氧性肺动脉高压小鼠模型中的作用(Aim 2)。这些目标将在Roy L.Sutliff博士和C.Michael Hart博士的指导下通过分子和药理实验来实现。这些结果旨在清楚地解决导致和帮助PH病理的分子机制。这笔NRSA拨款，加上我现有导师的帮助，以及埃默里大学提供的几个培训机会，这些博士前培训将用于扩大我在研究技术、实验设计和手稿写作方面的知识。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。