# Metabolic control of cellular differentiation and the fibrotic response

> **NIH NIH F32** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $65,310

## Abstract

PROJECT SUMMARY/ABSTRACT
Currently, more than 5 million Americans suffer from heart failure with approximately 500,000 new diagnoses
each year. In response to cardiac injury, a fibrotic response arises in an effort to maintain the structural and
functional integrity of the heart. Central to this healing response is the differentiation of fibroblasts to highly
specialized synthetic and contractile myofibroblasts. Unfortunately, the chronic nature of many cardiac diseases
is accompanied by the persistence of myofibroblasts and progressive fibrosis contributing to cardiac
decompensation and eventual failure. Therefore, it is important to identify the molecular mechanisms necessary
for myofibroblast formation and maintenance. Recent studies suggest that changes in cellular metabolism are
required for cellular remodeling and are associated with the induction of gene programs to support differentiation
in numerous cell types. Interestingly, changes in intermediary metabolism can alter the abundance of various
metabolites, some of which are essential to the function of epigenetic-modifying enzymes, such as DNA and
histone methyltransferases and demethylases. Indeed, epigenetic modifications are known to both silence and
promote gene transcription and differentiation programs, which may instigate the induction of the fibrotic gene
program. Therefore, we hypothesize that changes in intermediary metabolism are necessary for the epigenetic
reprogramming required for myofibroblast differentiation. Our preliminary data suggest that increased glycolytic
activity, as occurs during differentiation, is sufficient to promote myofibroblast differentiation, even in the absence
of pro-fibrotic stimuli. In addition, these changes in glycolysis are associated with alterations in the abundance
of key metabolites, some of which are required cofactors for specific epigenetic modifiers. In particular, α-
ketoglutarate levels are significantly increased upon TGF stimulation (canonical fibrotic agonist) and in
correlation we find a loss of H3K27me2 within the regulatory regions of known fibrotic genes. Preliminary data
suggests that H3K27 demethylation is dependent on the activity of a specific class of αKG-dependent, histone
KDMs (Jumonji C-domain containing histone demethylases). Here we will employ both metabolomic and
epigenomic approaches in gain- and loss-of-function model systems to examine the centrality of this process in
myofibroblast differentiation. This project will be the first to define how changes in intermediary metabolism are
directly linked to the transcriptional regulation mediating fibroblast differentiation.

## Key facts

- **NIH application ID:** 9859200
- **Project number:** 5F32HL145914-02
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Andrew A Gibb
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859200

## Citation

> US National Institutes of Health, RePORTER application 9859200, Metabolic control of cellular differentiation and the fibrotic response (5F32HL145914-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9859200. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*