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Gottlieb

Roberta A. Gottlieb, M.D.

Associate Professor, Division of Hematology, Molecular and Experimental Medicine, The Scripps Research Institute.

Research Interests

Programmed cell death, or apoptosis, is a stereotyped and tightly regulated physiologic process in cells where the outcome is self-destruction.  Myocardial ischemia results in death of cardiomyocytes through necrosis and apoptosis (1, 16). We are identifying specific biochemical events during ischemia-induced cell death which may serve as targets of therapeutic intervention (2-4). The Jun-N-terminal kinase (JNK) pathway is activated in response to myocardial ischemia and reperfusion, and using adenoviral-mediated gene transfer, have shown that the JNK pathway is essential for cardiomyocyte cell death following ischemia simulated by metabolic inhibition (5).  Cell death following ischemia may not depend less upon caspase activation, and more upon calpain cleavage, although Bid cleavage and mitochondrial release of cytochrome c are prominent features of both pathways (6,7). Generation of reactive oxygen species by damaged mitochondria contributes to myocardial injury, and calcineurin is one signaling molecule that contributes to mitochondrial dysfunction and increased ROS production (8). We are particularly interested in mitochondrial events during apoptosis (9-10, 15).  We have used the protein transduction domain of HIV TAT to deliver recombinant proteins to the isolated perfused heart and have shown that ARC, an anti-apoptotic molecule, can protect the heart against ischemia-reperfusion injury (11-13).  This approach of TAT-mediated protein transduction is quite successful and is now being applied to studies of Bnip3 and Bid, two pro-apoptotic BH3-only members of the Bcl-2 family (17).  Most recently we have become interested in the process of autophagy, which is the process by which a cell isolates an organelle or region of cytosol in a double-walled membrane and then targets it for destruction by fusion with a lysosome (17). Using fluorescent fusion proteins and high-resolution 3D-deconvolution microscopy, we can monitor mitochondrial events and autophagy in living cells (see Figure at right).  In separate work we have shown that inhibition of cytochrome P450 enzymes is also potently cardioprotective, even when the P450 inhibitors are administered after ischemia (14).  This may be due to suppression of ROS production or through inhibition of arachidonic acid metabolism. 

 

http://www.scripps.edu/mem/hema/gottlieb/

 
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