The epigenetic regulation of inflammation in tissue repair and vascular disease

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PROJECT SUMMARY The overarching theme for our research program over the past 10 years has been to better understand the etiology and pathogenesis of chronic inflammation in tissue repair processes and vascular disease, with a particular interest in how epigenetics influences the innate immune response and shapes pathologic and homeostatic processes. Our laboratory has contributed seminal studies related to 1) epigenetic regulation of myeloid cells that alter inflammation in abdominal aortic aneurysms (AAA), 2) regulation of macrophage phenotypes by chromatin modifying enzymes (CMEs) during tissue repair, 3) prostaglandin regulation of macrophage plasticity in the setting of tissue repair, 4) chemokines and other signaling pathways driving monocyte recruitment to injured tissue and tissue macrophage phenotypes, 5) epigenetic alterations that impact macrophage function in COVID-19 infection, 6) metabolomic and other biomarker studies in tissue regeneration and cardiovascular disease, 7) role of epigenetic regulation of macrophages following recovery from sepsis. Our work has utilized animal models to carry out mechanistic studies and patient-derived cells and tissues to confirm relevant pathways, identify therapeutic targets and characterize novel biomarkers. Based on our previously published observations and novel preliminary data, our laboratory is broadly focused in 4 main areas. The first serves as a continuation and expansion of HL156274 grant (currently in year 2) to complete and advance therapeutically relevant studies of JMJD3 and other critical CMEs in AAA development. The second goal will serve as renewal of HL137919 and allow us explore JAK/STAT signaling in tissue macrophages and blood monocytes and the downstream regulation of CMEs and subsequent inflammation in a variety of conditions (tissue regeneration, AAAs and post-sepsis recovery). The third goal will be to explore the interactions between structural cells (SMCs, keratinocytes, fibroblasts) and myeloid cells in the setting of tissue regeneration and AAA development. The fourth will be an expansion into the area of peripheral atherosclerosis where we will explore epigenetic regulation of macrophage phenotype/function in the setting of peripheral atherosclerotic disease (PAD). This emerging investigator award (EIA) mechanism will allow us to extend our studies in each of these areas and will allow for mechanistic understanding of the role of epigenetic regulation of macrophage phenotypes in the pathogenesis of a breadth of cardiovascular disease processes including tissue regeneration, aneurysm formation and peripheral atherosclerosis. It will also allow our laboratory to complete proof-of-concept and validation studies needed in both animals and humans to advance new therapies to the clinics for treatment of cardiovascular diseases.