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个人简介
Over the past 2 decades I have directed a translational research effort in the thematic area of cardiovascular remodeling with a particular focus upon heart failure. While the etiologies which promulgate heart failure can be diverse, there are some common structural underpinnings which include alterations in the extracellular matrix (ECM). My original studies in the 1980s using electron microscopy revealed that a disrupted/disorganized ECM was a common feature in cardiovascular disease. These observations led to the discovery that a specific family of ECM degrading enzymes, the matrix metalloproteinases (MMPs), emerged in patients with myocardial remodeling and heart failure. Through NIH funding, we have now identified that a large portfolio of MMPs are expressed in the progression of heart failure and are not associated with a parallel increase in the endogenous inhibitors of the MMPs (TIMPs). Using murine constructs, large animal pre-clinical models, and patient based studies, we have identified that a dysregulation between MMPs/TIMPs occurs early in the development of heart failure. Through pharmacological and transgenic approaches, we have established a cause-effect relation between increased MMP proteoltyic activity and adverse myocardial remodeling- particularly following a myocardial infarction (MI). Moreover, our clinical studies have demonstrated that the magnitude of MMP induction is directly related to the degree of late post-MI remodeling and the risk of heart failure. To that end, my recent work as been to focus upon developing diagnostic/prognostic biomarker panels of MMP/TIMPs, identifying the upstream regulatory pathways of MMP/TIMP induction, as well as to develop methods for post-translational regulation- ie MMP inhibition.
研究兴趣
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