# Exploring the Therapeutic Potential of BRD4 Extra-terminal Domain Inhibition in Cardiac Dysfunction and Remodeling. Fellow: Joshua Travers

> **NIH NIH F32** · UNIVERSITY OF COLORADO DENVER · 2020 · $65,310

## Abstract

Project Summary
Heart failure (HF), the final clinical manifestation of numerous cardiovascular pathologies, is a
devastating disease with poor prognosis. Nearly all etiologies of cardiovascular disease involve
pathological myocardial remodeling, characterized by excessive deposition of extracellular matrix
proteins by activated cardiac myofibroblasts, which reduces tissue compliance and accelerates HF
progression. Acetylation of nucleosomal lysine residues within chromatin represents an important
epigenetic regulatory mechanism of gene transcription that is critical to HF pathogenesis. In
particular, the acetyl-lysine reader protein BRD4 has been recognized for its significant contributions
to the transcription of pro-fibrotic gene programs, along with the development of cardiac dysfunction
and remodeling. Functional studies of BRD4 indicate that the extra-terminal (ET) domain mediates
transcriptional elongation of pro-fibrotic gene programs via interactions with co-factor proteins;
however, the potential for BRD4 ET domain inhibition in the treatment of cardiovascular disease has
yet to be elucidated. Utilizing innovative peptide inhibitors, the proposed studies will investigate the
therapeutic potential of BRD4 ET domain inhibition in primary cardiac fibroblasts and a murine model
of HF. The first aim will test the hypothesis that inhibition of the ET domain of BRD4 will alleviate
characteristics of pathological myofibroblast activation in primary mouse and human cardiac
fibroblasts, and chromatin immunoprecipitation sequencing will provide mechanistic insight into the
potential therapeutic properties of this inhibition. The second aim will evaluate the cardioprotective
properties of these novel BRD4 ET domain inhibitors in a clinically relevant pressure-overload model
of HF. Potential salutary properties on cardiac dysfunction will be assessed, along with the evaluation
of hypertrophy and fibrotic remodeling by histology and proteomic analysis of the extracellular matrix.
Finally, RNA-sequencing will be utilized to determine global gene expression alterations in the
myocardium in response to BRD4 ET domain inhibition. Importantly, the proposed work will
significantly enhance the applicant's skill sets in primary cell culture, cardiovascular physiology,
rodent models of HF, and the investigation of epigenetic mechanisms regulating gene transcription.
Together with the mentorship of a renowned expert in cardiovascular epigenetics committed to the
development of young scientists, this training will provide a solid foundation for the applicant's
development into an independent investigator. Moreover, this innovative approach offers the exciting
potential for the development of direly needed novel therapeutic strategies for the treatment of HF.

## Key facts

- **NIH application ID:** 9933821
- **Project number:** 5F32HL147463-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Joshua Travers
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 5
- **Project period:** 2019-04-10 → 2021-04-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933821

## Citation

> US National Institutes of Health, RePORTER application 9933821, Exploring the Therapeutic Potential of BRD4 Extra-terminal Domain Inhibition in Cardiac Dysfunction and Remodeling. Fellow: Joshua Travers (5F32HL147463-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9933821. Licensed CC0.

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