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

基本信息

批准号：
8763877
负责人：
Sherry Adesina
金额：
$ 3.02万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-19 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8763877
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 endothelial dysfunction 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

项目摘要

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（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 (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。本研究探讨了线粒体衍生的 ROS 与 NADPH 氧化酶活性产生的 ROS 之间的串扰在缺氧诱导的 PH 发展中的作用。 NADPH 氧化酶 (Noxes) 参与细胞 ROS 的产生，据信通过增加增殖来促进 PH 发病机制。一些研究还表明，线粒体 ROS 会导致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 发展/进展的机制仍未完全确定，但我们假设缺氧暴露会增加 ROS 的产生，这是由于线粒体和 Noxes 产生的 ROS 之间的串扰而发生的，这对 PH 的细胞有不同的影响。肺血管系统。这些ROS区室通过差异性地影响NADPH氧化酶、增殖基因和凋亡信号标记物的表达来影响缺氧诱导的增殖，从而差异性地调节血管重塑和可能的肺动脉高压。我们相信，调节 NADPH 氧化酶家族成员的表达或活性将提供一种新的机制，专门针对 ROS 的生成，预防内皮功能障碍和预防肺动脉高压。因此，该提案涉及两个具体目标：1）探索 ROS 源之间的串扰在缺氧诱导的内皮增殖、ROS 生成和细胞凋亡改变中的作用（目标 1），以及 2）确定线粒体之间串扰的作用。缺氧诱导的肺动脉高压新型小鼠模型中衍生的 ROS 和 Nox4（目标 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学实验来实现。这些结果旨在明确解决导致和辅助 PH 病理学的分子机制。这笔 NRSA 赠款资金，加上我既定导师的帮助，以及埃默里大学提供的一些培训机会，这种博士前培训将用于扩展我在研究技术、实验设计和手稿写作方面的知识。该奖项将为我成为一名独立学术研究员的长期目标做好准备。