# Epigenetic and Fetal Origins of Hypoxia-Induced Pulmonary Hypertension

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $388,750

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10133123
- **Project number:** 5R01HL138181-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Colleen Glyde Julian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2018-04-17 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133123

## Citation

> US National Institutes of Health, RePORTER application 10133123, Epigenetic and Fetal Origins of Hypoxia-Induced Pulmonary Hypertension (5R01HL138181-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133123. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*