Epigenetic and Fetal Origins of Hypoxia-Induced Pulmonary Hypertension

缺氧引起的肺动脉高压的表观遗传和胎儿起源

• 批准号: 9898437
• 负责人: Colleen Glyde Julian
• 金额: $ 41.7万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-17 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898437
• 关键词: Address; Affect; Age-Months; Altitude; Andean; Birth; Blood Vessels; Bolivia; Cell Differentiation process; Cells; Chronic; Colorado; Complex; DNA Methylation; Data Set; Development; Disease; Early Diagnosis; Elderly; Endothelium; Environmental Exposure; Enzymes; Epigenetic Process; Ethnic group; Etiology; Event; Exposure to; Expression Profiling; FRAP1 gene; Fetal Growth Retardation; Fetal Lung; Funding; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genetic Variation; Goals; Health; Human; Hypoxia; Impairment; Incidence; Individual; Infant; Knock-out; Knowledge; Life; Link; Longevity; Lung; Measures; Mediating; Medical Research; Methylation; Modeling; Modernization; Mononuclear; Morbidity - disease rate; Mus; Onset of illness; Outcome; Pathway interactions; Pattern; Perinatal Hypoxia; Persons; Pharmacology; Phenotype; Population; Pre-Eclampsia; Predisposition; Prevention strategy; Process; Prospective Studies; Proteins; Protocols documentation; Pulmonary Circulation; Pulmonary Heart Disease; Pulmonary Hypertension; Pulmonary artery structure; Race; Regulator Genes; Research; Respiratory physiology; Risk; Role; Sampling; Secondary to; Signal Transduction; Single Nucleotide Polymorphism; Site; Smooth Muscle Myocytes; Specimen; Structure; Structure of umbilical artery; Systolic Pressure; Testing; Time; Umbilical Cord Blood; United States National Institutes of Health; Validation; Vascular Diseases; Ventricular; Woman; Work; cell type; cohort; demethylation; early life exposure; epigenetic regulation; experience; fetal; genetic variant; hemodynamics; improved; indexing; infancy; mTOR Signaling Pathway; mTOR inhibition; metropolitan; mortality; mouse model; new therapeutic target; novel; offspring; prevent; prospective; pulmonary function; research facility; residence; sex; vascular smooth muscle cell proliferation; vasculogenesis

PROJECT SUMMARY Pulmonary hypertension (PH) is a progressive, life-threatening disease that often develops secondary to the chronic hypoxia of cardiopulmonary disease or high-altitude (HA) residence ( 2500m). Over the past few decades, PH-associated mortality has increased in both sexes of all race and ethnic groups, and no current therapy has proven effective for hypoxia-induced PH. Adverse intrauterine conditions, including fetal growth restriction (IUGR), preeclampsia and perinatal hypoxia, can induce durable changes to the structure and function of the lung and pulmonary vasculature, and are predictive of pulmonary vascular disease in affected offspring. Our overarching goal is to determine whether intrauterine growth restriction (IUGR) increases susceptibility to hypoxia-induced pulmonary hypertension by altering the epigenetic regulation of genes belonging to the mTOR pathway. To address this goal, we propose to conduct three integrated scientific aims. In Aim 1, we will define the effect of IUGR on mTOR pathway DNAm and gene expression patterns, and mTOR signaling in PBMCs and two representative vascular cell types (HUAECs and HUASMCs) at birth in humans using both primary and external validation cohorts. Our primary cohort will be infants born at LA or HA in Bolivia (400 and 3600 m), and our external validation cohort will consist of infants born in Frisco, Colorado to women living ≥ 3000m. Obtaining samples from Bolivia for our primary data set is beneficial because the La Paz metropolitan region comprises the largest, HA resident population in the world with more than two million persons living ≥ 3000m and the modern medical and research facilities necessary to conduct the proposed study aims; this will improve our efficiency with respect to obtaining a sufficient number of subjects for prospective study over the proposed timeframe. In Aim 2, we will establish the relationship between mTOR DNAm and expression patterns at birth and echocardiographic indices of PH measured prospectively across the first year of life (1 week, 6 and 12 months). Because DNAm marks are influenced by environmental and genetic factors, we will also determine whether differentially methylated mTOR pathway genes in cases of IUGR and/or PH during infancy, are associated with a) SNPs neighboring (< 500 kb) differential methylation marks, or b) SNPs within genes encoding proteins known to be involved in PH. Using this approach, we will determine the interactive effect of genetic factors, epigenetic marks and IUGR for PH. In Aim 3 we will use genetic and pharmacologic approaches in an established murine model of hypoxia-induced IUGR and PH to study the interaction of DNAm state, mTOR pathway signaling and IUGR for the developmental programming of pulmonary vascular dysfunction. Together, our research aims 1) address major knowledge gaps with respect to the mechanisms underlying the effect of intrauterine exposures to compromise the pulmonary circulation and 2) have the potential to identify targets for new therapeutic or preventive strategies to reduce the burden of pulmonary vascular disease across the lifespan.

项目总结 肺动脉高压(PH)是一种进行性的、危及生命的疾病，通常继发于 慢性低氧心肺疾病或高海拔(HA)住宅(2500m)。在过去的几年里 几十年来，与PH相关的死亡率在所有种族和民族的两性中都有所增加，目前没有 治疗已被证明对缺氧性肺高压有效。不利的宫内情况，包括胎儿生长 宫内发育迟缓(IUGR)、先兆子痫和围产期低氧可导致结构和功能的持久变化 肺和肺血管系统的功能，并预测受影响的肺血管疾病 后代。我们的首要目标是确定宫内生长受限(IUGR)是否增加 基因表观遗传调控改变对缺氧性肺动脉高压的易感性 属于mTOR途径。为了实现这一目标，我们提出了三个综合的科学目标。 在目标1中，我们将确定IUGR对mTOR途径dNaM和基因表达模式的影响，以及 小鼠外周血单个核细胞和两种具有代表性的血管细胞类型(HUAECs和HUASMCs)中的mTOR信号转导 同时使用主要验证队列和外部验证队列的人类。我们的主要人群将是在洛杉矶或HA出生的婴儿 在玻利维亚(400米和3600米)，我们的外部验证队列将包括在科罗拉多州弗里斯科出生的婴儿 女性生活在≥3000米。从玻利维亚获得主要数据集的样本是有益的，因为La PAZ大都市区拥有世界上最大的医管局常住人口，超过200万人 居住在≥3000米和现代医疗和研究设施所需的人 研究目标；这将提高我们在获得足够数量的主题方面的效率 在建议的时间范围内进行前瞻性研究。在目标2中，我们将建立mTOR之间的关系 DNaM、出生时表达模式和超声心动图指数前瞻性测量 出生第一年(1周、6个月和12个月)。因为dNaM标记受环境和环境的影响 遗传因素，我们还将确定差异甲基化的mTOR途径基因是否在 婴儿时期的IUGR和/或PH与a)邻近(500 Kb)差异甲基化的SNPs相关 标记，或b)编码已知与PH有关的蛋白质的基因中的SNPs。使用这种方法，我们将 确定遗传因素、表观遗传标记和IUGR对PH的交互作用。在《目标3》中，我们将使用 低氧诱导IUGR和PH小鼠模型的遗传学和药理学研究 研究dNaM状态、mTOR通路信号和IUGR在发育规划中的相互作用 肺血管功能障碍。总而言之，我们的研究目标是1)解决主要的知识差距 关于宫内暴露损害肺功能的潜在机制 循环和2)有可能确定新的治疗或预防战略的目标，以减少 一生中肺血管疾病的负担。