Joseph V. Bonventre, M.D. Ph.D.
Professor of Medicine

email jvbonventr@bics.bwh.harvard.edu, phone (617) 726-3770, fax (617) 726-4356. Lab home page:http://receptor.mgh.harvard.edu/Research/labs/bonventre/

Dr. Bonventre’s laboratory studies the mechanisms of cellular and tissue injury and repair, particularly as applied to ischemic injury to the kidney (ischemic acute renal failure, ARF ). Studies are performed at the molecular, cellular and whole organ levels. Techniques employed are those of molecular biology, immunofluorescence, biochemistry, biophysics and whole organ physiology.

Recent studies have revolved that adhesion molecules are very important for the pathophysiology of ARF. We have recently cloned a novel adhesion molecule that is expressed at very high levels during the recovery phase of ARF and in a model of chronic renal disease. Additional genes that are upregulated during repair have been identified.

A major focus of the lab is phospholipase A2 (PLA2) and the role of this family of enzymes on acute tissue injury, apoptosis, signal transduction and nuclear events including transcription. Using the yeast two- hybrid system we have identified a nuclear protein that interacts with the cytosolic 85 kDa cPLA2. We have created knock-out mice to study the function of PLA2s. Gene therapy approaches with adenovirus are being used. The role of stress- activated protein kinases and Ste- 20- like kinases in cellular injury are also being studied.

It is known that an eicosanoid product of cPLA2 and 5- lipoxygenase is a ligand for a transcription factor. Transcription factors are important determinants of the cellular repair processes after an ischemic insult to the kidney. A novel kidney-specific zinc finger transcriptional repressor, Kid-1, whose expression is regulated in renal ontogeny and by ischemia/ reperfusion was cloned and characterized. The Kruppel Associated Box-A (KRAB-A) motif of this and other zinc finger proteins was identified as a common repressor motif. We cloned a transcriptional repressor, KRIP-1, that interacts with KRAB-A. We are currently identifying proteins that associate with KRIP-1 to define mechanisms of transcriptional repression. This knowledge will help us understand the role that PLA2s play in injury and lead to better insight into mechanisms important for gene regulation governing cell proliferation, cell death and tissue repair after acute renal failure.

References:

1. Thadhani R., Pascual M., and Bonventre J. V. Acute renal failure. New Eng. J. Med. 334: 1448-1460. 1995

2. Sapirstein A., Spech R. A., Witzgall R., and Bonventre J. V. Cytosolic PLA2 (cPLA2), but not secretory PLA2, potentiates hydrogen peroxide cytotoxity in kidney epithelial cells. J. Biol. Chem. 271: 21505-21513, 1996

3. Kelly K. J., Williams Jr. W. W., Colvin R. B., Meehan S. M., Springer T. A., Gutierrez-Ramos J.-C. and Bonventre J. V. Intercellular adhesion molecule-1 deficient mice are protected against ischemic renal injury. J. Clin. Invest. 97: 1056-1063, 1996

4. Kim S-S, Chen Y-M, O’Leary E., Witzgall R., Vidal M., and Bonventre J. V. A novel member of the RING finger family, KRIP-1, associates with the KRAB-A transcriptional repressor domain of zinc finger proteins. Proc. Natl. Acad. Sci. USA. 93: 15299-15304, 1996.