# Small molecule therapies targeting chromatin architecture in heart failure

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2022 · $720,487

## Abstract

PROJECT SUMMARY/ABSTRACT
 Distinct transcriptomes in the heart’s different cell types enable adaptation in response to healthy
physiological demand and pathologic stress. Epigenomic machinery establishes the nuclear microenvironment
for such tailored gene regulation, shutting some genes off and turning others on, in a cell type-specific and
stimulus-responsive manner. However, the manner in which epigenomic remodeling underpins cardiac
hypertrophy and fibrosis and the spectrum of heart failure phenotypes observed clinically, including with reduced
ejection fraction (HFrEF; systolic dysfunction) or preserved EF (HFpEF; diastolic dysfunction), is unknown.
 Novel classes of epigenetic drugs like HDAC and BET-bromodomain inhibitor (i.e. agents that inhibit
chromatin readers) have shown great promise in preclinical studies of heart failure, and are now in a phase III
clinical trial to treat atherosclerosis, underscoring the tolerance of these drugs in humans and the potential of
developing epigenetic therapies to treat cardiovascular diseases. Further evidence that heart failure is
associated with a new, semi-stable and disease-promoting structural environment has come from genome
occupancy studies (using ChIP-seq), chromatin conformation capture studies, and analysis of DNA methylation.
These findings suggest that if the right subset of genomic loci could be targeted with designer drugs, a new class
of epigenomic therapies for the spectrum of heart failure might emerge.
 This multi-PI application is focused on pharmacologic manipulation of chromatin to identify novel targets
for the spectrum of heart failure. To unpack the role of different cell types, we will study epigenomic control in
myocytes and fibroblasts, examining distinct models of heart failure, including that resulting from salt, renal
dysfunction and hormonal imbalance (unilateral nephrectomized mice with a DOCA pellet and high salt) and
mice subjected to pressure overload by transverse aortic constriction, models of heart failure with preserved and
reduced ejection fraction, respectively. We hypothesize that epigenetic therapies targeting the intermediate
phenotypes of chromatin structure and accessibility afford a powerful opportunity to regulate entire gene
expression programs in a therapeutic manner to treat heart failure. Our experiments will characterize chromatin
structural changes in different cell types in models of systolic and diastolic dysfunction. We will conclusively
investigate the ability of small molecule epigenetic inhibitors to reverse disease-associated phenotypic and
chromatin architectural changes in animal models. Lastly, we will determine the mechanisms by which the
chromatin eraser family of HDACs and the chromatin reader BRD4 interact to regulate epigenomic architecture
and myocyte or fibroblast phenotype. Together, these investigations will validate a complementary class of heart
failure therapies in a cell type-specific manner, revealing the changes in chromat...

## Key facts

- **NIH application ID:** 10312765
- **Project number:** 5R01HL150225-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Timothy McKinsey
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $720,487
- **Award type:** 5
- **Project period:** 2019-12-15 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10312765

## Citation

> US National Institutes of Health, RePORTER application 10312765, Small molecule therapies targeting chromatin architecture in heart failure (5R01HL150225-03). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10312765. Licensed CC0.

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