[R01] Chromatin Regulation of Immune Cells in Myocardial Inflammation

Ente: National Heart Lung and Blood Institute

Scadenza: 2030-05-31

Importo max: 765.888 EUR

Paese: US

Descrizione

PROJECT SUMMARY Ischemic heart disease following myocardial infarction (MI) is a leading cause of global morbidity and mortality. During MI, infiltrating immune cells, particularly monocytes, differentiate into macrophages, adopting both reparative and maladaptive pro-inflammatory roles. These maladaptive immune responses can drive chronic inflammation, adverse remodeling, and ultimately heart failure (HF) progression. Although blocking monocyte recruitment has been explored as a therapeutic strategy, this approach risks impairing the essential reparative functions required for proper wound healing and scar formation post-MI. Thus, understanding chromatin and gene regulatory mechanisms controlling monocyte differentiation and macrophage activation is critical for developing therapies that selectively target maladaptive pro-inflammatory responses while preserving reparative functions. BRD4, a member of the BET protein family, is a key epigenetic regulator of chromatin dynamics and transcription during inflammation. Our preliminary data show that BRD4 plays a pivotal role in shaping pro-inflammatory macrophage phenotypes during MI. While pharmacological BET inhibition using JQ1 can reduce inflammation and improve cardiac function, systemic toxicity limits its therapeutic potential. To address this, we use a novel Brd4 conditional allele combined with the Ccr2creERT2 mouse model to achieve monocyte-specific BRD4 deletion. The goal of this project is to elucidate BRD4-mediated chromatin and gene regulatory networks (GRNs) that control monocyte differentiation and macrophage function during MI and to identify therapeutic strategies that selectively modulate maladaptive inflammation. Aim 1 will define how Brd4 deletion in CCR2+ monocytes affects macrophage fate and cardiac function post-MI, using flow cytometry and scRNA-seq to track macrophage differentiation and assess physiological impacts. Aim 2 will investigate BRD4’s role in regulating macrophage activation, combining CUT&RUN and CRISPR interference to map BRD4 binding and its influence on MHC-II gene expression and other pro-inflammatory programs. Aim 3 will use proteomics to identify BRD4 protein interactors in macrophages, focusing on PU.1, to understand how it modulates BRD4 function during pro- inflammatory activation. This work will generate a comprehensive map of BRD4-regulated transcriptional and chromatin dynamics in immune cells, providing new therapeutic targets that limit maladaptive macrophage activation, reduce chronic inflammation, and improve outcomes in HF patients. Istituzione: J. DAVID GLADSTONE INSTITUTES PI: Michael Alexanian Progetto: 5R01HL181372-02

Settori: National Heart Lung and Blood Institute

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