# Novel Approaches to Assess Metabolic Dysregulation in Pulmonary Hypertension

> **NIH VA IK2** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

Pulmonary hypertension (PH), an increasingly common condition characterized by progressive remodeling of
the pulmonary vasculature, is an incurable disorder associated with significant morbidity and mortality. In a
large retrospective cohort of >100,000 veterans diagnosed with PH, we recently reported that PH related to
underlying heart (Group 2), or lung (Group 3) disease was most common and associated with the worst
prognosis. Strikingly, existing therapies for PH are neither effective nor indicated in these common PH
subgroups. Our preliminary studies highlight broad metabolic dysregulation in mice, rats, and subjects with
Group 3 PH. Because existing therapies fail to reverse underlying metabolic derangements that cause
pulmonary vascular cell proliferation and remodeling, this proposal seeks to better defining underlying
mechanisms of metabolic dysregulation in PH. Circulating platelets will be used as a unique biosensor to
study mitochondrial and metabolic dysfunction in PH. The PI will use bioinformatics to integrate the
experimental results with PH clinical features. We hypothesize that analysis of platelet bioenergetics and
metabolic function will reflect similar alterations in pulmonary vascular cells and serve as a metabolic
biosensor for evaluation of PH pathogenesis, progression, and treatment. This hypothesis will be examined in
two specific aims using sera, platelets, and pulmonary artery smooth muscle cells (PASMC) from
experimental and clinical samples. Aim 1 will explore critical hubs of metabolic dysregulation in
PASMCs and platelets isolated from PH rats. The Sugen 5416-hypoxia rat model will be employed to
isolate PASMCs and platelets from control and PH animals. The PI will be trained to characterize PH in this
model measuring hemodynamics, vascular remodeling, and right ventricular hypertrophy. Mitochondrial
function will be defined in PASMCs and platelets using an array of assays established in the mentor's lab.
Advanced metabolomics and isotope tracing for targeted metabolite analysis will be conducted under the
training of the Co-Mentor. Temporal changes in these parameters over time will be integrated with
hemodynamics and vascular remodeling. Aim 2 will examine mitochondrial and metabolic dysregulation
in de-identified platelets and plasma from clinically phenotype Group 3 PH patients. Platelets and
plasma from Group 3 PH, and age-matched controls will be subjected to mitochondrial and metabolomic
studies described in Aim 1. Bioinformatics approaches will elucidate if co-morbidities correlate with alterations
in metabolic hubs using multi-scale associations between participant characteristics, bioenergetic, and
metabolomic data. These findings will inform critical pathways of metabolic dysregulation that may be
therapeutically targeted to improve outcomes in PH. These studies and career development activities will
provide an exceptional foundation for the PI to become a successful, independently funded VA scientist to
...

## Key facts

- **NIH application ID:** 10699009
- **Project number:** 1IK2BX005913-01A2
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Matthew Ryan Smith
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2023-10-01 → 2028-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10699009

## Citation

> US National Institutes of Health, RePORTER application 10699009, Novel Approaches to Assess Metabolic Dysregulation in Pulmonary Hypertension (1IK2BX005913-01A2). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10699009. Licensed CC0.

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