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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要慢性宫内缺氧不仅在中国1.4亿人中很常见世界各地生活在高海拔地区，但也存在许多妊娠并发症，如先兆子痫、吸烟和胎盘功能不全导致胎儿对慢性缺氧的适应。导致许多不良发育结果，包括新生儿肺动脉高压。 BKCa 通道对于新生儿肺血管系统的舒张至关重要我们建立的慢性缺氧胎儿羔羊模型的最新结果。妊娠表明 BKCa 通道功能障碍是肺动脉高压的一个致病因素。该提案中的工作将研究细胞缺氧和 BKCa 之间的机制联系其他人最近的研究表明“主要的hypoxamir”miR210，一个被 HIF-1 上调的 micro-RNA 通过抑制铁硫簇组装蛋白 ISCU 的翻译导致铁硫的缺乏。我们发现慢性宫内缺氧会导致线粒体功能障碍。通过激活 HIF-1 → miR210 → ISCU 轴导致肺动脉高压，导致线粒体衍生的活性氧物质增加，从而导致 BKCa 通道功能障碍。我们提出了三个具体目标。每个具体目标都旨在整合体外和体内。体内方法，以便更好地确定体外结果与肺的相关性目标 1 将重点确定 BKCa 的潜在机制。通道功能障碍，并确定 BKCa 通道功能单独丧失是否是足以导致完整羔羊的肺动脉高压。目标 2 将重点关注以下因素的影响：缺氧诱导 miR210 对 ISCU 活性、铁硫簇水平和在完整的羔羊中，我们将了解线粒体功能和活性氧的产生。确定在缺氧的情况下该通路的激活是否会导致肺损伤高血压，以及在缺氧的情况下抑制该通路是否可以预防 BKCa 目标3将调查通道功能和肺动脉高压是否增加。慢性缺氧反应的活性氧水平在 BKCa 中起致病作用我们将使用体外和体内方法。确定是全局抗氧化剂维生素C还是线粒体特异性抗氧化剂MitoQ 可预防慢性宫内缺氧引起的肺动脉高压。