Despite current standard of care, a diagnosis of heart failure (HF) is associated with poor quality-of-life and a 5-year mortality approaching 50%. In light of this urgent unmet need, the elucidation of novel mechanisms involved in HF pathogenesis holds promise for identifying new therapies for this prevalent and deadly disease. The PIs of this application were the first to illustrate a crucial role for a conserved family of acetyl-lysine ?reader? proteins (BET bromodomains) in the transcriptional control of HF. Importantly, these studies leveraged the use of JQ1, a first-in-class, specific small molecule inhibitor of BET bromodomains. This multi-PI renewal application seeks to vertically advance our understanding of how aberrant chromatin-dependent signal transduction (via the BET family member BRD4) drives pathologic cardiac fibrosis. Our long-term objective is to develop BRD4 inhibition as a novel therapeutic strategy in HF. Exciting preliminary studies demonstrate that BRD4 mediates cardiac fibroblast activation in vitro, and that BRD4 inhibition with JQ1 suppresses cardiac fibrosis in mouse models of HF. Mechanistically, we demonstrate that BRD4 functions downstream of pro- fibrotic TGF-? signaling by binding to regulatory enhancers that drive a gene program of myofibroblast (myoFB) activation. This proposal will test the central hypothesis that BRD4 functions as a nodal transcriptional regulator of pathological cardiac fibrosis that can be pharmacologically targeted in vivo. Guided by strong preliminary data, this hypothesis will be tested by pursuing three robust specific aims: (1) Discover the gene-specific role of BRD4 in cardiac myoFB in vivo; (2) Dissect the chromatin-dependent signaling mechanisms governing BRD4-dependent activation of endogenous cardiac myoFBs; (3) Define the roles of specific BRD4 functional domains in the control of cardiac myoFB activation. Several innovative tools that were developed during the first funding period will be employed to advance this new avenue of investigation, including floxed Brd4 mice, Brd4-3XFLAG knock-in mice, Brd4 bromodomain knock-in mice, as well as peptides and small molecules that selectively inhibit distinct functional domains in BRD4. The proposed research is significant because it will facilitate development of pharmacologic BRD4 inhibition as a novel therapeutic strategy in HF, and therefore addresses an enormous unmet clinical need. Our proposal is highly innovative because we successfully ?drug? pro-fibrotic transcription and remodeling via unprecedented approaches, we define the functions of BRD4 in cardiac fibroblasts for the first time, and we provide the first epigenomic evaluation of cardiac fibroblasts. Given the synergistic expertise of our consortium, we envision that sustained contributions from our highly-collaborative group will pave the way for the development of novel ?epigenetic therapies? for cardiovascular disease.
The proposed research is relevant to public health because developing novel treatment approaches for heart failure represents an urgent unmet societal need in the United States. Thus, the proposed research is highly relevant to the NHLBI's mission to support medical research on heart failure, which affects 6 million people in the United States and is a leading cause of mortality, hospitalization, and healthcare expenditures in our country. This proposed research is relevant to NIH's mission to seek fundamental knowledge that will help to enhance health and reduce the burden of human illness and disability.
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