[R01] Epigenomic mechanisms of cardiac fibrosis and heart failure

Ente: National Heart Lung and Blood Institute

Scadenza: 2029-05-31

Importo max: 773.842 EUR

Paese: US

Descrizione

PROJECT SUMMARY A heart failure diagnosis leads to poor quality of life and a 5-year mortality nearing 50%, underscoring the urgent need for innovative treatments. Clinical evidence strongly links myocardial fibrosis, driven by pathological activation of cardiac fibroblasts, with unfavorable outcomes in heart failure patients. Prior efforts to control fibrosis often targeted signaling pathways, integrins, or extracellular matrix components, affecting many tissues. However, much less is known about the epigenomic mechanisms governing cardiac fibrosis and fibroblast activation. Understanding these mechanisms could lead to more targeted therapies. We previously showed that pharmacological inhibition of bromodomain and extra-terminal (BET) proteins, key mediators of stress-activated chromatin signaling, alleviates cardiac dysfunction and fibrosis in mouse heart failure models. Single-cell genomics demonstrated that BET inhibition suppresses fibroblast activation and profibrotic gene programs. One of the most BET-sensitive genes, Meox1, is minimally expressed in healthy hearts but highly upregulated in activated fibroblasts during heart failure. Single-cell transcriptomics also showed significant MEOX1 upregulation in human heart failure. In fibroblasts treated with TGFβ, MEOX1 inhibition reduced profibrotic functions and expression of stress-responsive gene programs. Notably, fibroblast-specific Meox1 deletion in vivo in mice mitigates transverse aortic constriction (TAC)-induced cardiac dysfunction and decreases fibroblast activation, highlighting MEOX1’s potential as a therapeutic target. This proposal consists of two aims leveraging novel genetic mouse models, cell lines, and advanced transcriptional, epigenomic, and computational approaches to test the overall hypothesis that MEOX1 functions as a key transcriptional regulator of fibroblast activation, fibrosis, and heart failure pathogenesis. Aim 1 will examine the impact of fibroblast-specific Meox1 deletion on cardiac fibrosis and heart failure in mice, with single-cell analysis revealing global transcriptional changes. Aim 2 will investigate the role MEOX1-target regulatory elements and genes in fibroblast activation and utilize a newly developed cellular tool to map MEOX1 occupancy and histone marks in human cardiac fibroblasts, uncovering the MEOX1-dependent gene-regulatory networks driving fibroblast activation. These studies will provide a definitive answer to whether MEOX1 is a central regulator of fibroblast activation and fibrosis in heart failure, delivering vital insights into the molecular mechanisms driving fibroblast activation and identifying potential therapeutic targets. Istituzione: J. DAVID GLADSTONE INSTITUTES PI: Michael Alexanian Progetto: 5R01HL175312-02

Settori: National Heart Lung and Blood Institute

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