Department of Cell, Developmental and Integrative Biology
McGill University, Montreal, Canada
Texas Tech University Health Sciences Center, Lubbock, TX
PhD, Pharmacology, 1985
University of British Columbia, Vancouver, Canada
Postdoctoral Fellow, 1985-8
Washington University School of Medicine, St. Louis, MO
Postdoctoral Fellow, 1991-3
Dr. Ramanadham’s research interests include study of programmed death (apoptosis) of insulin-secreting ß-cells in the pancreatic islet, involvement of a novel enzyme activity in bone formation, and HIV-protease inhibitor-induced metabolic abnormalities. Brief descriptions of these areas are provided below:
1. iPLA2ß and ß-Cell Apoptosis. Diabetes mellitus (DM) is the most prevalent human metabolic disease, and it results from loss and/or dysfunction of ß-cells in pancreatic islets. ß-Cell mass is regulated by a balance between ß-cell growth, resulting from ß-cell replication and neogenesis, and ß-cell death resulting from apoptosis. Accumulating evidence suggests that ß-cell apoptosis contributes to the pathophysiology in both types 1 and 2 diabetes mellitus. It is therefore important to understand the mechanisms underlying ß-cell apoptosis if this process is to be prevented or delayed. We recently identified participation of a Ca2+-independent phospholipase A2 in ß-cell apoptosis and the goals of this project are to understand the mechanism by which lipid mediators contribute to ß-cell death.
2. iPLA2ß and Bone Formation. Bioactive arachidonic acid (AA) metabolites (eicosanoids) generated by the actions of 5-lipoxygenase (5-LO) and cyclooxygenase (COX) are important mediators of bone remodeling. The 5-LO products leukotrienes and 5-HETE (hydroxyeicosa-tetraenoic acid) function as negative modulators of bone formation by inhibiting osteoblast differentiation and bone formation. In contrast, prostaglandins (PGs), e.g., PGE2, derived from metabolism of AA by cyclooxygenase (COX), enhance bone formation and mass by increasing osteoblast replication and differentiation and/or by inhibiting osteoclastic resorption, although high concentrations of PGE2 can stimulate bone resorption. Dietary supplementation with AA results in increases in bone mass and volume, which reflects a beneficial role of eicosanoids in bone formation. Our studies reveal abnormalities in bone formation in iPLA2ß-null mice and the goals of this project are to elucidate the role of iPLA2ß in bone formation.
3. HIV-PIs and Insulin Resistance/Diabetes. Over the past two decades, the number of people worldwide living with HIV/AIDS has risen to nearly 40 million. The introduction of PIs in 1995 has resulted in marked decreases in mortality among HIV+ patients from 30% achieved with RTs combination therapy alone to 8% with the addition of a PI. The beneficial effects of PIs in combination with NRTIs/NNRTIs are evidenced by the dramatic decreases in HIV plasma viremia, marked reductions in opportunistic infections, and in mortality and morbidity among HIV+ patients. However, inclusion of PIs in the therapeutic regimen is also associated with peripheral lipoatrophy, visceral adiposity, hyperlipidemia, insulin resistance, hyperglycemia, and overt type 2 diabetes mellitus. The development of these metabolic complications, analogous to The Metabolic Syndrome may be affected by multiple factors but they are reported to occur in 60-80% of HIV+ patients treated with PIs and are associated with significant risk for cardiovascular disorders in these patients. Our studies indicate the involvement of a novel signaling cascade in PI-Induced insulin resistance and diabetes and the goals of this project are to describe the mechanism(s) by which chronic PI treatments induce metabolic abnormalities.
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