Molecular Basis of Fibrosis: Development of Epidrug for Fibrosis Therapy.  Hyperactivity of differentiated fibroblasts causes an excessive synthesis and deposition of extracellular matrix proteins in the tissues that leads to fibrosis in multiple organs, a major cause of disease-related morbidity and mortality worldwide. Fibrosis is a common end-stage pathological symptom of a wide spectrum of injury or stress related multi-organ diseases such as hypertension-induced accelerated cardiovascular disease, chronic kidney disease, liver cirrhosis, systemic sclerosis and pulmonary disease. Epigenetics plays a key role in the development of multi-organ fibrosis. Our research interest focuses on the role of acetyltransferase p300, a major epigenetic regulator, in TGF-b-induced profibrogenic signal transduction and organ fibrosis. We have previously demonstrated that acetyltransferase p300 is an essential epigenetic regulator for profibrogenic signal-induced matrix protein collagen synthesis. Most importantly, the levels of p300 are significantly elevated in myofibroblasts derived from resident fibroblasts or vascular endothelial cells in response to TGF-beta and different fibrotic tissues. We are interested to determine i) the molecular basis of p300 elevation in fibrotic tissues; ii) the contribution of elevated level of p300 in cardiac, renal and pulmonary fibrogenesis; iii) epigenetics in cardiac and renal endothelial-to-mesenchymal transition (EndMT), cellular proliferation, migration and senescence; and iv) to develop novel epigenetic therapeutic approaches targeting acetyltransferase activity of p300 to control cardiac, renal and lung fibrosis. We are testing the therapeutic efficacies of novel small molecule inhibitors of epigenetic regulator acetyltransferase p300 for prevention and reversal of stress-induced accelerated cardiac, renal and lung aging-associated pathologies using murine models. We are also testing the efficacy of a drug-like small molecule inhibitor targeting plasminogen activator inhibitor-1 in amelioration of air pollutant PM_2.5-induced lung and heart disease. The research is funded by grants from American Heart Association and National Institutes of Health.