Professor, Departments of Cell Biology & Medicine
The Dr. Gerald and Myra Dorros Chair in Cardiovascular Disease
Director, Wilf Family Cardiovascular Research Institute
Office: Forchheimer G46
Lab: Golding Bldg., G01
||Key Words: cell death/apoptosis/necrosis/heart disease/cancer/diabetes
Cell Death: Fundamental Mechanisms and Roles in Human Disease
My lab studies (a) fundamental mechanisms of cell death and (b) the roles of cell death in human disease. Over the past 20 years, we have elucidated basic aspects of cell death biology, in particular delineating mechanisms by which the cell death inhibitor ARC antagonizes both the intrinsic and extrinsic death pathways (Molecular Cell, 2004. 15: 901-912; PNAS, 2007. 104: 20826-20831; JBC, 2007. 282: 5522-5528; JBC, 2007. 282: 5529-5535; others). Interestingly, we have discovered roles for ARC not only in heart disease, but also in cancer (Cell Death Differ, 2005; Cancer Res, 2011. 71: 7705-7715), pulmonary hypertension (Circulation, 2011. 124: 2533-2342), and type 2 diabetes (Diabetes, 2013: 62: 183-193).
Our most important translational accomplishments have focused on cell death in the heart. I was one of the founders of the cardiac cell death field and have played a leading role in its development. My lab was the first to demonstrate that regulated forms of cell death play a central role in the pathogenesis of myocardial infarction (J Mol Cell Cardiol, 2000. 32: 2397-2402 and others). In addition, we provided the first evidence that cell death is a causal component in the pathogenesis of heart failure (J Clin Invest, 2003. 111: 1497-1504 and others).
Presently, our work is focused on: (a) understanding mechanistic connections that link cell death programs - in particular, apoptosis and necrosis (PNAS, 2012. 109: 6566-6571; Cell Death Differ, 2014. 21: 634-644); and molecular connections between cell death and other mitochondrial processes. One of these processes, which plays important roles in aging and disease, is mitophagy, the selective elimination of senescent and damaged mitochondria by a specialized form of macroautophagy. Recently, we have discovered new roles for cell death molecules as regulators of mitophagy. (b) A second major focus in the lab employs chemical and structural approaches in the identification/design of small molecules to reduce cardiomyocyte death. We have used both unbiased screening (Probe Reports from the NIH Molecular Libraries Program, 2013; PMID: 24404634) and candidate approaches to develop prototypes of what we hope will become small molecule drugs to reduce heart damage during myocardial infarction.
I supervise a laboratory of approximately 8, including Ph.D. and M.D./Ph.D. students and postdocs. An important facet of my work is training and mentorship. I have been thesis research advisor to 11 individuals who have received the Ph.D. degree. A significant proportion of my trainees have gone on to academic faculty positions as independent investigators. My pre- and postdoctoral trainees have included a substantial number of individuals from groups under-represented in science.