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

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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 provide a solid foundation for the applicant’s development into an independent investigator. Moreover, this innovative approach offers the exciting potential to contribute to the development of desperately needed novel therapeutic strategies for the treatment of heart failure.