# Administrative Core

> **NIH NIH P01** · FLORIDA INTERNATIONAL UNIVERSITY · 2023 · $117,115

## Abstract

PROGRAM SUMMARY
Pulmonary vascular disease (PVD) is perhaps the most important complication for children with congenital heart
disease (CHD) that results in increased pulmonary blood flow (PBF) and pressure. Postnatally, the presence of
large communications at the level of the ventricles (e.g. ventricular septal defect) or great vessels (e.g. truncus
arteriosus) exposes the pulmonary circulation to abnormal elevations in blood flow and pressure, which results
in progressive structural and functional abnormalities of the pulmonary vasculature. Metabolic reprogramming is
increasingly recognized as a critical component of early pulmonary vascular injury and disease. Vascular
morphology studies in our Shunt lamb model demonstrate a >2-fold increase in pulmonary arterioles in Shunt
compared to control lambs. This is opposed to the decrease in arterial counts demonstrated in humans with
advanced disease. This early increase in angiogenesis likely represents an adaptation to the increase in flow
and pressure. The development of a hyperproliferative, anti-apoptotic endothelial phenotype is necessary for this
angiogenic response. Further, it requires a dramatic metabolic reprogramming that serves to supply these cells
with the necessary biosynthetic precursors required for cell division while simultaneously decreasing cellular
ATP levels due to increased consumption and decreased respiration. We have linked this decrease in ATP to
the loss of hsp90-mediated NO signaling and the development of endothelial dysfunction and vascular
remodeling. Thus, this PPG intensely focuses on increasing our understanding of: i) the differential effects of
mechanical forces on cellular metabolic programming; ii) post translational modifications (PTMs) that influence
key signaling pathways involved in metabolic reprogramming; iii) interactions between mitochondrial network
dynamics, metabolism, and cellular survival; iv) how these pathways interact to disrupt hsp90-mediated NO
signaling; and v) novel therapeutic strategies for treating CHD with increased PBF. The key novel pathways that
comprise the focus of each Project were identified by our intensive investigations into the metabolic
reprogramming underlying the development of pulmonary vascular disease and selected for their capacity to
contribute to a spectrum of cellular responses related to glutaminolysis and aerobic glycolysis (Project #1),
cellular ß-oxidation and mitochondrial bioenergetics (Project #2), mitochondrial network dynamics and
mitophagy (Project #3), and cell proliferation and apoptosis (Projects #1 & #3). Investigations are integrated
across our three PPG projects to fully understand how metabolic reprogramming leads to the loss of hsp90-
mediated NO signaling and represents the thematic underpinning of this PPG. The synergy derived from the
interactions between individual Projects and scientific Cores, with our programmatic approaches, will promote
an increased understanding of how mechanical forces ...

## Key facts

- **NIH application ID:** 10705681
- **Project number:** 5P01HL146369-05
- **Recipient organization:** FLORIDA INTERNATIONAL UNIVERSITY
- **Principal Investigator:** Stephen M Black
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $117,115
- **Award type:** 5
- **Project period:** 2020-08-20 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10705681

## Citation

> US National Institutes of Health, RePORTER application 10705681, Administrative Core (5P01HL146369-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10705681. Licensed CC0.

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