# Post-translational modifications & mitochondrial bioenergetics

> **NIH NIH P01** · FLORIDA INTERNATIONAL UNIVERSITY · 2023 · $434,182

## Abstract

PROJECT SUMMARY
Approximately 1% of children are born with a congenital heart defect, with half requiring medical and/or surgical
treatment. Children born with congenital heart defects that result in increased pulmonary blood flow (PBF) and
pressure develop abnormal pulmonary vascular reactivity. Although survival for these children has improved
they continue to suffer morbidity and late mortality. This is due to the fact that they are at great risk for developing
pulmonary vascular disease. In fact, even early pulmonary endothelial dysfunction, with abnormal vascular
reactivity, causes significant morbidity and mortality. From our ongoing studies, it has become clear that there is
an intimate, and complex, relationship between cellular metabolism and endothelial NO synthase (eNOS)
signaling. However, how these processes are linked is unresolved and unravelling novel connections will be the
major goal of this Project. Our group is at the fore-front of investigating the role played by post-translational
modifications (PTMs) in the metabolic reprogramming associated with pulmonary vascular disease. The overall
hypothesis we will test in this project is that PTMs play a major role in the metabolic reprogramming and loss
of NO signaling associated with increased PBF and pressure. Using an experimental lamb model of CHD with
increased PBF (Shunt), we have found that the mitochondrial redistribution of eNOS leads to the disruption of
mitochondrial bioenergetics. Further, the resulting decrease in ATP generation leads to the proteasomal
degradation of GTP cyclohydrolase I (GCH1), the rate limiting enzyme in the generation of the important NOS
co-factor, tetrahydrobiopterin (BH4), secondary to the loss of hsp90 activity. We have identified the relevant E3
ubiquitin ligase as the carboxy-terminus of Hsc70 interacting protein (CHIP). However, a significant knowledge
gap exists in our understanding of how mechanical forces induce the mitochondrial redistribution of eNOS and
the activation of CHIP. Specific Aim 1 will fill this important gap by investigating the role played by the PTM-
mediated activation of Akt1 and identifying ubiquitin proteasome pathway (UPP) components that are stimulated
by mechanical forces. The tyrosine kinase, pp60Src is also chaperoned by hsp90 and has been shown to regulate
mitochondrial bioenergetics. However, its role in regulating endothelial cell metabolism is not known. Thus,
Specific Aim 2 will investigate whether the attenuation of mitochondrial bioenergetics associated with increased
PBF and pressure also involves a decrease in pp60Src activity. To begin the clinical translation of our basic
investigations, Specific Aim 3 will utilize our Shunt lamb model to determine if preserving mitochondrial
bioenergetics or inhibiting the proteasome are therapeutic targets for enhancing NO signaling and endothelial
function in children born with congenital heart defects that increase PBF and pressure. The successful
completion of our ...

## Key facts

- **NIH application ID:** 10705698
- **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:** $434,182
- **Award type:** 5
- **Project period:** 2020-08-20 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10705698

## Citation

> US National Institutes of Health, RePORTER application 10705698, Post-translational modifications & mitochondrial bioenergetics (5P01HL146369-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10705698. Licensed CC0.

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