Raphael Zidovetzki
Professor of Cell Biology & Neuroscience
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Physical Biochemistry Signal Transduction
Ph.D., The Weizmann Institute of Science, Rehovot, Israel, 1980
VOICE: 951-827-5628 |
A variety of biological stimuli (e.g., hormones, growth factors, antigens) act via a pathway involving increased lipid metabolism. One of the products of the increased lipid metabolism, diacyglycerol (DAG), serves as an intracellular "second messenger" activating such membrane-associated enzymes as protein kinase C and phospholipases and resulting in the biological response of the cell to the original stimulus. Dr. Zidovetzki's research group is studying molecular details of DAG-induced activation of these enzymes using primarily nuclear magnetic resonance (NMR) and specific enzymatic assays. The group has identified the types of bilayer perturbations which are associated with the increased activity of protein kinase C and phospholipase A2. They have also found differ-ences between protein kinase C and phospholipase A2 in their response to certain types of the membrane structural defects. The obtained results provide information on the finely tuned mechanisms of the regulation of the responses of the two key enzymes by relatively small variations in DAG-induced changes in lipid membrane structure and point toward a new direction for pharmacological intervention with these responses. Indeed, Dr. Zidovetzki's team has shown that the anti-malarial drug chloroquine, which does not strongly interact with lipid membranes, "stabilizes" the bilayers against DAG- induced pertubations preventing activation of phospholipase A2. This phospholipase A2 inhibition may play a role in the anti-inflammatory and anti-malarial effects of this drug.
Dr. Zidovetzki is currently applying the information obtained using biophysical methods to studying the mechanisms of transmembrane signal transduction in human central nervous system (CNS)-derived endothelial cells affected by 1) ischemic stroke risk factors, such as hypertension and nicotine, and 2) HIV infection. The results show that HIV-derived TAT protein has a profound effect on the activity of protein kinase A in human endothelial cells which may be relevant to the cyropathological effects of HIV in the brain. Future researth on this project will involve monitoring the activities of such intracellular enzymes as protein kinase C, phospholipase A2, phospholipase C and sphingomyelinase in response to nicotine or TAT in combination with such cytokines as tumor necrosis factor and interleukin 1. This interaction will establish a connection between inflammatory cytokines and the disruption of the blood brain barrier under particular risk conditions resulting in the pathological conditions observed in AIDS encephalitis or ischemic stroke.
SELECTED PUBLICATIONS
Goldberg, D.M. and Zidovetzki, R. Synergistic effects of diacylglycerols and fatty acids on membrane structure and protein kinase C activity. Biochemistry 37:5623-5632 (1998).
Zidovetzki, R., Wang, J.-L., Chen, P., Jeyaseelan, R. and Hofman, F. Human immunodeficiency virus tat protein induces interleukin-6 mRNA expression in human brain endothelial cells via protein kinase C- and cAMP-dependent protein kinase pathways. AIDS Res. Human Retroviruses 14:873-878 (1998).
Goldberg, E.M. and Zidovetzki, R. Effects of dipalmitoylglycerol and fatty acids on membrane structure and protein kinase C activity. Biophys. J. 73:2603-2614 (1997).
Zidovetzki, R. Membrane properties and the activation of protein kinase C and phospholipase A2. Current Topics in Membranes 44:255-283, (1997).
Zidovetzki, R., Sherman, I.W., Prudhomme, J. and Crawford, J. Inhibition of plasmodium falciparum lysophospholipase by antimalarial drugs and sulfhydryl reagents. Parasitology 108:249-255 (1994).