Oxidant Signaling in Pulmonary Hypertension

肺动脉高压中的氧化信号

• 批准号: 10720584
• 负责人: THOMAS C RESTA
• 金额: $ 58.62万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-10 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720584
• 关键词: Acute; Agonist; Airway Disease; Altitude; Animal Model; Blood; Cell Proliferation; Cell membrane; Cell model; Cholesterol; Cholesterol Homeostasis; Chronic; Chronic Bronchitis; Chronic Obstructive Pulmonary Disease; Clinical; Couples; Coupling; Data; Disease; Distal; Edema; Electron Transport; Epidermal Growth Factor Receptor; Functional disorder; G-Protein-Coupled Receptors; Generations; Heart; Hypoxia; Impairment; Knowledge; Laboratories; Link; Lung; Lung diseases; Maintenance; Mechanics; Mediating; Membrane; Microfilaments; Mission; Mitochondria; Morbidity - disease rate; Mus; NADPH Oxidase; National Heart, Lung, and Blood Institute; Oxidants; Pathway interactions; Patients; Peripheral; Pilot Projects; Population; Preparation; Preventive measure; Process; Production; Progressive Disease; Proliferating; Pulmonary Circulation; Pulmonary Emphysema; Pulmonary Heart Disease; Pulmonary Hypertension; Pulmonary arterial remodeling; Rare Diseases; Reactive Oxygen Species; Regulation; Research; Rodent Model; Role; Scaffolding Protein; Signal Pathway; Signal Transduction; Sleep Apnea Syndromes; Sleep Disorders; Smooth Muscle Myocytes; Source; Stimulus; Stretching; Testing; Tissue Model; Vascular Diseases; Vascular resistance; Vasoconstrictor Agents; World Health Organization; arterial remodeling; caveolin 1; cholesterol trafficking; constriction; effective therapy; genetic approach; human model; hypoxia-induced pulmonary hypertension; innovation; lung hypoxia; mitochondrial dysfunction; mitochondrial membrane; mortality; new therapeutic target; novel; novel strategies; novel therapeutic intervention; pharmacologic; pulmonary arterial hypertension; pulmonary vascular disorder; pulmonary vasoconstriction; response; right ventricular failure; src-Family Kinases; uptake; vasoconstriction

PROJECT SUMMARY Pulmonary vascular dysfunction resulting from chronic hypoxia (CH) leads to increased vascular resistance and resultant pulmonary hypertension (PH) in patients with chronic obstructive pulmonary diseases, sleep ap- nea, restrictive lung diseases, and in residents at high altitude. The resulting increase in afterload on the right heart often leads to clinical manifestations of cor pulmonale, peripheral edema, morbidity and mortality. Alt- hough it is widely considered that pulmonary arterial constriction and remodeling are central to this disease process, the mechanisms linking CH to these responses are poorly understood. The overall objective of the current study is to identify oxidant signaling mechanisms responsible for spon- taneous pulmonary arterial smooth muscle cell (PASMC) tone and enhanced vasoconstrictor reactivity in CH- induced PH. Based on preliminary data, our central hypothesis is that PASMC Cav1 dysfunction following CH disrupts cellular cholesterol homeostasis that confers transduction of mechanical, electrical and GPCR stimuli to mitochondrial Ca2+ uniporter (MCU)-dependent mitochondrial reactive oxygen species (mtROS) generation, vasoconstriction, and pHTN. We plan to test this hypothesis by pursuing the following specific aims: Specific Aim #1: Establish the mechanism by which CH reduces PASMC membrane cholesterol leading to enhanced vasoconstrictor reactivity and cell proliferation. Hypothesis: CH couples vasoconstrictor stimuli to PASMC myofilament Ca2+ sensitization and proliferation through impaired Cav1-mediated cholesterol trafficking to the cell membrane. Specific Aim #2: Define the signaling mechanism by which CH increases PASMC mtROS generation, vaso- constriction, and cell proliferation. Hypothesis: Cav1 dysfunction following CH causes mitochondrial membrane cholesterol accumulation and MCU-dependent mtROS generation required for augmented PASMC contractility and proliferation. Specific Aim #3: Determine the contribution of Cav1, MCU and mtROS to CH-induced pHTN. Hypothesis: Cav1 dysregulation and MCU-induced mtROS production contribute to the progression and maintenance of CH-induced pHTN. We anticipate this project will define an innovative paradigm of PASMC signaling involving regulation of mtROS generation and Ca2+ sensitization by Cav1-mediated disruption of cellular cholesterol homeostasis that is unique to the pulmonary circulation. The proposed studies are significant because they are expected to ver- tically impact our understanding of regulation of oxidant signaling mechanisms by Cav1 and membrane cho- lesterol, and their contribution to CH-induced pHTN. In doing so, they have potential to provide new thera- peutic strategies to treat pHTN that target components of this signaling pathway.

项目摘要 慢性缺氧（CH）导致的肺血管功能障碍导致血管阻力增加 慢性阻塞性肺疾病患者的肺动脉高压（PH），睡眠呼吸暂停综合征（AP）， nea、限制性肺病和高海拔地区居民。右侧后负荷的增加 心脏病常导致肺心病的临床表现，周围水肿，发病率和死亡率。替代- 尽管人们普遍认为肺动脉收缩和重构是该病的核心 过程中，连接CH这些反应的机制知之甚少。 目前研究的总体目标是确定负责Spon的氧化剂信号传导机制， 在CH中，肺动脉平滑肌细胞（PASMC）张力和血管收缩反应性增强。 基于初步数据，我们的中心假设是CH后PASMC Cav 1功能障碍 破坏细胞胆固醇稳态，从而赋予机械、电和GPCR刺激的转导 线粒体Ca 2+单向转运体（MCU）依赖的线粒体活性氧（mtROS）产生， 血管收缩和pHTN。我们计划通过追求以下具体目标来检验这一假设： 具体目标#1：确定CH降低PASMC膜胆固醇的机制， 增强血管收缩反应性和细胞增殖。 假设：CH将血管收缩刺激与PASMC肌丝Ca 2+增敏和增殖偶联 通过受损的Cav 1介导的胆固醇运输到细胞膜。 具体目标#2：定义CH增加PASMC mtROS生成的信号传导机制， 收缩和细胞增殖。 假设：CH后Cav 1功能障碍导致线粒体膜胆固醇积聚， 增加PASMC收缩性和增殖所需的MCU依赖性mtROS生成。 具体目标#3：确定Cav 1、MCU和mtROS对CH诱导的pHTN的贡献。 假设：Cav 1失调和MCU诱导的mtROS产生有助于病情进展， CH诱导的pHTN的维持。 我们预计，该项目将定义一个创新的范式PASMC信号，涉及调节 Cav 1介导的细胞胆固醇稳态破坏导致线粒体ROS生成和Ca 2+敏化， 是肺循环所特有的拟议的研究是重要的，因为他们预计将ver- 这将影响我们对Cav 1和膜胆固醇调节氧化剂信号传导机制的理解。 胆固醇，以及它们对CH诱导的pHTN的贡献。在这样做的过程中，它们有可能提供新的治疗方法， 治疗pHTN的治疗策略，靶向该信号通路的组分。