Research Associate Professor of Medicine
Sasanka Ramanadham is an Associate Professor (Research) of Medicine at Washington University School of Medicine. He received his B.Sc. from McGill University in Canada and his Ph.D. from Texas Tech University Health Sciences Center in Texas. He joined Washington University in 1991 and currently runs a laboratory located on the 8th Floor of SW Tower. Dr. Ramanadham interests include study of ER stress-induced b-cell apoptosis, of involvement of novel enzyme in bone formation, and of HIV-protease inhibitor-induced metabolic abnormalities.
Our areas of research include:
1. iPLA2β and β-Cell Apoptosis. Diabetes mellitus (DM) is the most prevalent human metabolic disease, and it results from loss and/or dysfunction of β-cells in pancreatic islets. Autopsy studies indicate that the β-cell mass in obese T2DM patients is smaller than that in obese non-diabetic subjects and that the loss in β-cell function in non-obese T2DM is also associated with decreases in β-cell mass. β-Cell mass is regulated by a balance between β-cell growth, resulting from β-cell replication and neogenesis, and β-cell death resulting from apoptosis. Findings in both rodent models of T2DM and in human T2DM have now led to the conclusion that the decrease in β-cell mass in T2DM is not attributable to reduced β-cell proliferation or neogenesis but to increased β-cell apoptosis. It is therefore important to understand the mechanisms underlying β-cell apoptosis if this process is to be prevented or delayed. We recently identified participation of a Ca2+-independent phospholipase A2 in β-cell apoptosis and the goals of this project are to understand the mechanism of its involvement.
2. iPLA2β 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 (hydroxyeicosatetraenoic 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 iPLA2β-null mice and the goals of this project are to elucidate the role of iPLA2β 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