# Elucidating the Molecular Mechanisms and Cellular Specificity of HDAC Inhibitor Efficacy in Diastolic Dysfunction

> **NIH NIH K99** · UNIVERSITY OF COLORADO DENVER · 2024 · $106,921

## Abstract

PROJECT SUMMARY
Diastolic dysfunction (DD), characterized by impaired left ventricular compliance and relaxation, is associated
with increased risk of developing heart failure with preserved ejection fraction (HFpEF), a devastating syndrome
with poor prognosis for which there currently exist limited therapeutic interventions. Dynamic acetylation of
histones represents a critical component of chromatin-dependent signal transduction involved in the activation
of cardiac fibroblasts (CFs) and increased extracellular matrix deposition, leading to progressive DD and
development of HFpEF. These processes are largely regulated by histone deacetylases (HDACs), a family of
epigenetic regulatory enzymes whose pharmacological inhibition is cardioprotective in the setting of DD;
however, little is known regarding the HDAC isoform specificity and molecular mechanisms mediating this
protection. This Pathway to Independence award will leverage innovative small molecule inhibitors, genetics-
based strategies for cell type-specific gene ablation, and the integration of multifaceted state-of-the-art
epigenomic and bioinformatics techniques to examine the cell type- and isoform-specificity of HDAC inhibition
(Aims 1 and 2), and therapeutic potential of inhibition of a novel glycan binding protein (Aim 3), in myofibroblast
activation, cardiac fibrosis and DD. In Aims 1 and 2, the applicant will train with co-mentors and advisors in the
K99 phase in a single-cell, genome-wide next generation sequencing technology that characterizes chromatin
architecture, a flow cytometry-based technique for characterizing inflammatory cells, an integrated approach to
transcriptomics and proteomics analyses in primary human CFs, and a genetics-based approach for cell type-
specific gene ablation, all with the overall goal of defining the cellular specificity and molecular mechanisms
mediating the cardioprotective properties of HDAC inhibition. In the R00 phase described in Aim 3, the applicant
will utilize the skills acquired in the K99 phase to investigate the role and therapeutic potential of inhibiting the
glycan-binding protein Galectin-1, recently discovered to be significantly altered in the CF population of mice
with DD and subjected to HDAC inhibition, in myofibroblast activation, cardiac remodeling, and the progression
to HFpEF. The applicant possesses extensive prior knowledge in epigenetics, CF biology, and the
pathophysiology of DD and fibrotic remodeling. Furthermore, the mentorship team consists of internationally
recognized leaders in epigenetic regulation of cardiovascular disease, clinical HFpEF, murine models of HF, and
emerging bioinformatics technologies. The environment at the University of Colorado Anschutz Medical Campus
is exemplary for collaborative and innovative research, with an excellent infrastructure including a human heart
biorepository and outstanding core facilities. In summary, the exceptional mentoring team and institutional
environment will provid...

## Key facts

- **NIH application ID:** 10845643
- **Project number:** 5K99HL166708-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Joshua Travers
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $106,921
- **Award type:** 5
- **Project period:** 2023-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10845643

## Citation

> US National Institutes of Health, RePORTER application 10845643, Elucidating the Molecular Mechanisms and Cellular Specificity of HDAC Inhibitor Efficacy in Diastolic Dysfunction (5K99HL166708-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10845643. Licensed CC0.

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