# Protein acetylation-dependent fatty acid metabolic dysfunction in HFpEF

> **NIH NIH K08** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $147,673

## Abstract

Project Summary
Heart failure with preserved ejection fraction (HFpEF) accounts for ≈50% of all patients with heart failure, and is
associated with significant morbidity, mortality, and health care expenditures. Yet, no effective treatment for
HFpEF has been identified. Commonly coexisting with other metabolic diseases, HFpEF is considered the
cardiovascular manifestation of a systemic metabolic disturbance. However, little is known about its underlying
mechanisms. Our laboratory recently developed and validated a novel mouse model that faithfully recapitulates
most clinical features of human HFpEF. Using this novel mouse model, I discovered significant mitochondrial
dysfunction in HFpEF myocardium, which is associated with mitochondrial protein hyperacetylation, a key post-
translational modification known to regulate enzymatic activities. This led to our central hypothesis that protein
hyperacetylation is a reversible driver of mitochondrial dysfunction and metabolic remodeling in HFpEF and could
serve as a meaningful therapeutic target. In this proposal, we aim to (1) Determine the role of Sirtuin 3, the major
mitochondrial deacetylase, in regulating mitochondrial function and HFpEF pathogenesis; (2) Identify specific
targets through which hyperacetylation impacts mitochondrial function in HFpEF; (3) Determine the therapeutic
effect of modulating protein acetylation on HFpEF mitochondrial function and cardiac phenotype. Collectively,
these studies will have a meaningful impact on our understanding of HFpEF pathophysiology and potentially
unveil novel therapy to effectively treat HFpEF. Furthermore, work proposed here, coupled with a comprehensive
training plan, will provide me with the additional knowledge and skills required to launch my career as a
successful and fully independent physician-scientist.

## Key facts

- **NIH application ID:** 10369549
- **Project number:** 1K08HL157697-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Dan Tong
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $147,673
- **Award type:** 1
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10369549

## Citation

> US National Institutes of Health, RePORTER application 10369549, Protein acetylation-dependent fatty acid metabolic dysfunction in HFpEF (1K08HL157697-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10369549. Licensed CC0.

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