# Interventions Against the Molecular Etiology of BMPR2-induced PAH

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $662,881

## Abstract

Project Summary:
ACE2 shows tremendous promise in the treatment of pulmonary arterial hypertension (PAH). It
corrects many of the molecular defects caused by the most common heritable cause of disease,
BMPR2 mutation. It has reversed disease in a variety of animal models of PAH, including heritable,
hypoxic, and inflammatory models. We have tested it acutely in human idiopathic PAH patients, and
shown a variety of hemodynamic and molecular improvements, including a 40% improvement in
cardiac output with associated reduction in pulmonary vascular resistance. Unfortunately, because of
difficulties with both synthesis and delivery, it will be difficult to translate to common use.
Understanding key mediators of its effect is thus the primary barrier to effective translation of this
extraordinarily promising intervention. The proposed studies will identify the key molecular
mechanisms of downstream effect of ACE2 in the context of PAH, in regulation of the cytoskeleton
(aim 1), metabolism (aim 2), and improvements in right ventricle function in the heart (aim 3). The
unifying hypothesis to these aims is that ACE2’s therapeutic effect is primarily through MAS1-
mediated correction of cytoskeletal defects caused by suppressed BMPR2. These defects include
cell-cell junctions, mitochondrial dynamics, and regulation of eNOS. The project makes use of genetic
mouse models, including a new far-red reporter mouse which allows non-invasive imaging of heart
stress, patient-derived endothelial precursor cells, our new artificial arteriole system which accurately
reproduces pulse pressure, stiffness, flow, and shear in a cell culture system, thus combining human,
mouse, and new cell culture systems to answer these questions.

## Key facts

- **NIH application ID:** 9869025
- **Project number:** 5R01HL095797-11
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** JAMES D WEST
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $662,881
- **Award type:** 5
- **Project period:** 2019-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869025

## Citation

> US National Institutes of Health, RePORTER application 9869025, Interventions Against the Molecular Etiology of BMPR2-induced PAH (5R01HL095797-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9869025. Licensed CC0.

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