MANJERI A.
VENKATACHALAM, M.B., B.S.
Professor
Phone (voice): 210 567 4108
E-mail: venkatachal@uthscsa.edu
Degrees
1962, M.B., B.S., Calcutta Medical College, and Calcutta
University, India
1957, I.Sc., St. Xavier's College, and Calcutta
University, India
Postdoctoral Training
1967-68, Chief Resident, Mallory Institute of Pathology,
Boston City Hospital, and Teaching Fellow, Harvard Medical School
1964-67, Assistant Resident, and Assistant Instructor, State
University of New York
1963-64, House Physician, Medical College Hospitals, Calcutta,
India
1962, Clinical Assistant, Medical College Hospitals,
Calcutta, India
Description of
Research
My research is aimed at elucidating the structural, biochemical and molecular
mechanisms of cell death that occurs in the context of hypoxia. This type of
injury is of much clinical significance because of its occurrence during and
after ischemia of tissues and organs in human disease. Working mainly with
cultured kidney cells subjected to hypoxia or metabolically induced energy
depletion, we have identified a major mechanism of cell damage that is caused
by loss of cell associated glycine. Glycine, a small neutral amino acid that is
transported to high concentrations within cells under normal conditions, is
lost to the extracellular milieu when energy is not available. A unique form of
plasma membrane damage results as a consequence of this loss, and this is
prevented by the provision of exogenous glycine. Our studies have shown that
the development of glycine sensitive membrane damage does not require increases
of extracellular calcium, and that optimal availability of glycine allows cells
to tolerate increases of cytosolic ionized calcium to levels previously thought
to be not possible, and yet survive and proliferate. Structure-activity
relationships of related amino acids and other pharmacological studies suggest
that glycine may target its actions on a plasma membrane protein that is
related to ligand gated chloride channel receptors in the central nervous
system. On going studies are focused on developing strategies to identify the
molecular target of glycine cytoprotection.
In related collaborative studies with Dr. P. Saikumar, we have used glycine to
preserve cell structure during prolonged periods of hypoxia, and examined the
consequences of reoxygenation. Reoxygenation damage has been ascribed to
overproduction of oxygen free radicals. Our studies show that hypoxia induces
the translocation of Bax, a death promoting protein, from cytosol to
mitochondria, with concomitant release of cytochrome c from mitochondria to the
cytosol. Reoxygenation resulted in cell death with apoptotic morphology, but
molecular oxygen was not required for this process, and cell death was
prevented by inhibitors of the caspase family of cysteine proteases. Bcl-2, an
anti-apoptotic protein, did not prevent Bax translocation, but inhibited
cytochrome c release and cell death, and caspase inhibitors prevented
apoptosis, but not cytochrome c release. These intriguing findings have spawned
a new research effort in our laboratory, aimed at the role played by the
interactions of Bcl-2 and Bax in determining mitochondrial integrity during
energy deprivation and the critical period of reoxygenation when they might
tilt the outcome between recovery or apoptosis.
Selected References
Weinberg JM, Davis JA,
Garza-Quintero R, Weinberg JM, Ortega-Lopez J, Davis JA,