Training: • Baccalaureate I, II, 1962: Paris, France
• B.S., 1966: University of California at Los Angeles
• M.S., NIH, Immunology, 1966-1968 (Bruce Merchant, M.D., Ph.D., mentor)
• Ph.D., 1970: Indiana University School of Medicine, Indianapolis, IN.
(J.S. Ingraham, Ph.D.)
•
Post Doctoral, 1970-1971: Pasteur Institut, Paris, France
(Jacques Pillot, M.D., Ph.D.)
•
Sabbatical Leave, 1990: Fred Hutchinson Cancer Research Center,
Seattle, WA. (John Hansen, M.D.) Summary of the focus of the research of Dr. Brahmi:
Dr. Brahmi's laboratory is dedicated to research in tumor immunology. More specifically, they have been investigating signal transduction in cytolytic lymphocytes (NK cells and CTL) exposed to sensitive tumor targets (TC). They have previously shown that NK and CTL cells lose their lytic potential after contact with TC and this loss of activity is accompanied by the rapid down- regulation of mRNA encoding perforin, granzyme B and TNFa, whereas constitutively expressed messages such as b-actin, GAPDH or CHO-B are not downregulated. They have also demonstrated that multiple elements governing perforin mRNA stability reside within the coding region, a novel type of mRNA regulation not previously reported in eukaryotes. To further investigate the relevance of mRNA loss, they have stably transfected NK and CTL cells with perforin and granzyme B plasmid constructs, two lytic molecules involved in the granule-mediated lytic pathway. These constructs demonstrated no lytic activity against sensitive TC by the Fas lytic pathway, but retained their ability to lyse Fas positive TC by the Fas lytic pathway. They are also investigating the relevance of apoptosis and programmed cell death in the replication of RNA viruses such as VSV and FIV. They have shown that, contrary to accepted dogma, granzyme B induces apoptosis and degrades viral RNA in infected targets suggesting that granzyme B can work independently of perforin. RNA viruses in infected, Fas positive target cells treated with anti-Fas are also inactivated, but the mechanism of inactivation is still unknown but seems to involve caspases. Work is in progress to elucidate the mechanism that leads to this viral degradation and its biological significance. Publications:
Bajpai, A. and Brahmi, Z. 1994. Target cell-directed inactivation of cytolytic lymphocytes: role and regulation of phosphatases. The Journal of Biological Chemistry 269, 18864-18869. Su, B., Bochan, M., Hanna, W., Froelich, C. and Brahmi, Z. 1994. Human granzyme B is essential for DNA fragmentation of susceptible target cells. European Journal of Immunology 24, 2073-2080. Bochan, M., Goebel, S. and Brahmi, Z. 1995. Stably transfected antisense granzyme B and perforin constructs inhibit human cytotoxic cell potential. Cellular Immunology 164, 234-239. Goebel, S., Schloemer, R. and Brahmi, Z. 1995. Target cell-induced perofrin mRNA in NK3.3 cells is mediated by multiple elements within the mRNA coding region. Molecular Immunology 33, 341-349. Montel, A., Hommel-Berrey, G. and Brahmi, Z. 1997. Fas-mediated cytotoxicity induces degradation of vesicular stomatitis virus RNA transcripts and reduces viral titer. Molecular Immunology 34, 1055-1066.
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