Mechanisms of newborn pulmonary hypertension caused by chronic intrauterine hypoxia

慢性宫内缺氧引起新生儿肺动脉高压的机制

• 批准号: 10366534
• 负责人: Arlin B Blood
• 金额: $ 79.75万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366534
• 关键词: Acclimatization; Address; Adult; Altitude; Animal Model; Animals; Antioxidants; Ascorbic Acid; Attenuated; Birth; Blood Vessels; Blood flow; Blood gas; Calcium; Cell Hypoxia; Chronic; Communication; Development; Disease; Electron Microscopy; Epigenetic Process; Exposure to; Fetal Development; Fetal Sheep; Fetus; Flow Cytometry; Functional disorder; Gene Expression; HIF1A gene; Hypoxia; Image; In Situ; In Vitro; Incidence; Iron; Lead; Link; Lung; Measures; Mediating; Methodology; Methods; MicroRNAs; Mitochondria; Modality; Molecular; Myography; Neonatal; Newborn Infant; Outcome; Oxidative Stress; Pathogenicity; Pathway interactions; Persons; Pharmacology; Placental Insufficiency; Play; Potassium Channel; Pre-Eclampsia; Predisposing Factor; Pregnancy; Pregnancy Complications; Pregnant sheep; Production; Proteins; Pulmonary Hypertension; Pulmonary artery structure; Reactive Oxygen Species; Relaxation; Rodent; Role; Ryanodine Receptor Calcium Release Channel; Sheep; Stress; Sulfur; Sulofenur; Term Birth; Testing; Therapeutic; Tissues; Translations; Vasodilation; Work; antioxidant therapy; cigarette smoking; design; fetal; fetus hypoxia; gestational hypoxia; hypoxia inducible factor 1; hypoxia-induced pulmonary hypertension; in utero; in vivo; knock-down; lamb model; large-conductance calcium-activated potassium channels; mitochondrial dysfunction; mortality; neonatal outcome; neonatal pulmonary hypertension; novel; patch clamp; postnatal; prevent; pulmonary function; response

PROJECT SUMMARY Chronic intrauterine hypoxia is common amongst not only the 140 million people in the world living at high altitudes but also in many complications of pregnancy such as preeclampsia, cigarette smoking, and placental insufficiency. Adaptation of the fetus to chronic hypoxia results in many adverse developmental outcomes, including pulmonary hypertension of the newborn. The BKCa channel is critical to the relaxation of the pulmonary vasculature of the newborn at birth. Recent results from our well-established fetal lamb model of chronic hypoxia during pregnancy points to BKCa channel dysfunction as a causal factor in pulmonary hypertension. The work in this proposal will investigate the mechanistic link between cellular hypoxia and BKCa channel dysfunction. Recent work by others indicates that the ‘master hypoxamir’ miR210, a micro-RNA that is upregulated by HIF-1?, orchestrates pulmonary hypertension by suppressing translation of the iron-sulfur cluster assembly protein ISCU. The resulting lack of iron-sulfur clusters results in mitochondrial dysfunction. We hypothesize that chronic intrauterine hypoxia leads to pulmonary hypertension by activation of the HIF-1? → miR210 → ISCU axis, resulting in increased mitochondrial-derived reactive oxygen species that lead to BKCa channel dysfunction. We propose three specific aims. Each specific aim is designed to integrate in vitro and in vivo approaches in order to better ascertain the relevance of the in vitro results to pulmonary function of the intact animal. Aim 1 will focus on determining the mechanism underlying BKCa channel dysfunction, and on establishing whether loss of BKCa channel function alone is adequate to result in pulmonary hypertension in intact lambs. Aim 2 will focus on the effects of hypoxia-induced increases in miR210 on ISCU activity, iron-sulfur cluster levels, and mitochondrial function and reactive oxygen species production. In intact lambs, we will establish whether activation of this pathway in the absence of hypoxia results in pulmonary hypertension, and whether suppression of this pathway in the presence of hypoxia prevents BKCa channel function and pulmonary hypertension. Aim 3 will investigate whether the increased reactive oxygen species levels in response to chronic hypoxia play a causative role in BKCa channel function and pulmonary hypertension. Using both in vitro and in vivo methods, we will determine whether the global antioxidant Vitamin C or mitochondria-specific antioxidant MitoQ will prevent pulmonary hypertension caused by chronic intrauterine hypoxia.

项目摘要 慢性宫内缺氧不仅在1.4亿人中很常见 居住在高海拔地区的世界，但也处于许多怀孕的并发症，例如先兆子痫， 吸烟和斑点功能不全。胎儿适应慢性缺氧结果 在许多不良发育结果中，包括新生儿的肺动脉高压。 BKCA通道对于放松新生儿肺脉管系统至关重要 生日。我们成熟的胎儿羔羊模型的慢性缺氧模型的最新结果 怀孕指向BKCA通道功能障碍是肺动脉高压的因子。这 该提案中的工作将研究细胞缺氧与BKCA之间的机械联系 通道功能障碍。其他人最近的工作表明“大师hardoxamir” mir210，一个 由HIF-1上调的微RNA，通过抑制来编排肺动脉高压 铁硫簇组装蛋白ISCU的翻译。导致缺乏铁硫 簇导致线粒体功能障碍。我们假设慢性插入缺氧 通过激活HIF-1导致肺动脉高压？ →miR210→iscu轴， 导致导致BKCA通道的线粒体衍生的活性氧增加 功能障碍。 我们提出了三个具体目标。每个特定目标旨在整合体外和 体内方法以更好地确定体外结果与肺的相关性 完整动物的功能。 AIM 1将专注于确定BKCA的机制 通道功能障碍，并确定BKCA频道功能是否损失是否为 AIM 2将集中于分析完整羔羊肺动脉高压的结果。 缺氧引起的MiR210在ISCU活性，铁硫簇水平和 线粒体功能和活性氧的产生。在完整的羔羊中，我们将 确定在没有缺氧的情况下激活该途径是否导致肺 高血压，以及在缺氧存在下对该途径的抑制是否会阻止BKCA 通道功能和肺动脉高压。 AIM 3将调查是否增加 响应慢性缺氧的活性氧水平在BKCA中起因作用 通道功能和肺动脉高压。使用体外和体内方法，我们将 确定全球抗氧化剂维生素C或线粒体特异性抗氧化剂MITOQ是 将预防由慢性插入缺氧引起的肺动脉高压。