Epigenetic and Fetal Origins of Hypoxia-Induced Pulmonary Hypertension

缺氧性肺动脉高压的表观遗传和胎儿起源

基本信息

批准号：
10133123
负责人：
Colleen Glyde Julian
金额：
$ 38.88万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-17 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10133123
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 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 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

项目摘要

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.

项目概要肺动脉高压 (PH) 是一种进行性、危及生命的疾病，通常继发于肺动脉高压心肺疾病或高海拔（HA）居住（≥2500m）的慢性缺氧。几十年来，所有种族和族裔群体中，与 PH 相关的死亡率均有所增加，而且目前没有治疗已被证明对缺氧引起的宫内不良状况（包括胎儿生长）有效。限制（IUGR）、先兆子痫和围产期缺氧，可引起结构和功能的持久变化。肺和肺血管系统的功能，并且可以预测受影响的肺血管疾病我们的首要目标是确定宫内生长受限 (IUGR) 是否增加。通过改变基因的表观遗传调控对缺氧引起的肺动脉高压的易感性为了实现这一目标，我们建议实现三个综合科学目标。在目标 1 中，我们将定义 IUGR 对 mTOR 通路 DNAm 和基因表达模式的影响，以及出生时 PBMC 和两种代表性血管细胞类型（HUAEC 和 HUASMC）中的 mTOR 信号传导使用主要和外部验证队列的人类我们的主要队列将是在洛杉矶或HA出生的婴儿。在玻利维亚（400 和 3600 m），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从玻利维亚获取样本作为我们的主要数据集是有益的，因为 La。巴斯大都市区拥有世界上最大的 HA 常住人口，超过 200 万居住面积≥3000m的人员以及进行拟议的研究所需的现代化医疗和研究设施研究目标；这将提高我们获得足够数量的受试者的效率在目标 2 中，我们将建立 mTOR 之间的关系。出生时的 DNAm 和表达模式以及前瞻性测量的 PH 超声心动图指数生命第一年（1周、6个月和12个月）因为DNAm标记受环境和影响。遗传因素，我们还将确定 mTOR 通路基因是否存在差异甲基化婴儿期的 IUGR 和/或 PH 与 a) 邻近 (< 500 kb) 差异甲基化的 SNP 相关标记，或 b) 编码已知参与 PH 的蛋白质的基因内的 SNP，我们将使用这种方法。确定遗传因素、表观遗传标记和 IUGR 对 PH 的交互影响。已建立的缺氧诱导的 IUGR 和 PH 小鼠模型中的遗传和药理学方法研究 DNAm 状态、mTOR 通路信号传导和 IUGR 之间的相互作用以进行发育编程总之，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 2）有可能确定新的治疗或预防策略的目标，以减少肺血管疾病的负担贯穿整个生命周期。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An Aptitude for Altitude: Are Epigenomic Processes Involved?

DOI：
10.3389/fphys.2019.01397
发表时间：
2019-11
期刊：
Frontiers in Physiology
影响因子：
4
作者：
C. Julian
通讯作者：
C. Julian

How hypoxia slows fetal growth: insights from high altitude.

DOI：
10.1038/s41390-021-01784-0
发表时间：
2022-01
期刊：
Pediatric research
影响因子：
3.6
作者：
Moore LG
通讯作者：
Moore LG

Vascular Disorders of Pregnancy Increase Susceptibility to Neonatal Pulmonary Hypertension in High-Altitude Populations.

DOI：
10.1161/hypertensionaha.122.19078
发表时间：
2022-06
期刊：
HYPERTENSION
影响因子：
8.3
作者：
Heath-Freudenthal, Alexandra;Toledo-Jaldin, Lilian;von Alvensleben, Inge;Lazo-Vega, Litzi;Mizutani, Rodrigo;Stalker, Margaret;Yasini, Hussna;Mendizabal, Fanny;Madera, Jesus Dorado;Mundo, William;Castro-Monrroy, Melany;Houck, Julie A.;Moreno-Aramayo, Any;Miranda-Garrido, Valquiria;Su, Emily J.;Giussani, Dino A.;Abman, Steven H.;Moore, Lorna G.;Julian, Colleen G.
通讯作者：
Julian, Colleen G.

Effect of high altitude on human placental amino acid transport.

高海拔对人胎盘氨基酸转运的影响。

DOI：
10.1152/japplphysiol.00691.2019
发表时间：
2020
期刊：
Journal of applied physiology (Bethesda, Md. : 1985)
影响因子：
0
作者：
Vaughan,OwenR;Thompson,Fredrick;Lorca,RamónA;Julian,ColleenG;Powell,TheresaL;Moore,LornaG;Jansson,Thomas
通讯作者：
Jansson,Thomas

AMP-activated protein kinase activator AICAR attenuates hypoxia-induced murine fetal growth restriction in part by improving uterine artery blood flow.