Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Small molecule therapies targeting chromatin architecture in heart failure


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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 chromatin accessibility and structure that underpin pathologic gene expression in clinically distinct forms of heart failure.
Collapse sponsor award id
R01HL150225

Collapse Time 
Collapse start date
2019-12-15
Collapse end date
2023-11-30

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