University of Alabama at Birmingham, USA
Dr. Ramanadham was awarded his PhD from the Department of Pharmacology at Texas Tech University Health Sciences Center in 1985. He thesis project focused on cardiovascular complications associated with diabetes. He has continued work in the diabetes area and is now engaged in studies to understand the contribution of lipid singnaling to type 1 diabetes development. He has nearly 100 publications, serves on Journal Editorial Boards, and as a grant reviewer for both National and Intenational Diabetes Foundations. He is currently a Professor in the Department of Cell, Developmental, and Integrative Biology, and a Senior Scientist in the Comprehesive Diabetes Center at UAB.
Type 1 diabetes (T1D) is a consequence of pancreatic islet b-cell destr uction, due to apoptosis . Our lab is in vestigating underlying mechanisms that contribute to b-cell loss and we identified a prominent role for the group VIA Ca2+-independent phosphoplipase A2b (iPLA2b) in this process. The cytosolic iPLA2b catalyzes hydrolysis of the sn-2 sbstituent from membrane phopsholipids . The islet b-cell membranes are enriched in arachidonate-containing phospholipids and activation of iPLA2b in the b-cells leads to accumulations in arachidonic acid and its various oxidized metabolites (i.e. eicosanoids). The eicosanoids manifest different activities, some of which are proinflammatory and apoptotic and some are ant-inflammatory and anti-apoptotic. Inhibition, knockdown, or knockout of iPLA2b significantly reduces b-cell apopotosis due to ER stress or proinflammatory cytokines. Further, d uring the development of autoimmune T1D, expression and activity of iPLA2b increases and this is associated with generation of proinflammatory and apoptotic lipid signals. Consistent with this, we find that with selective inhibition of iPLA2b in the spontaneously diabetes-prone non-obese diabetic (NOD) mouse, there is a significant reduction in islet infiltration by leukocyte s, preservation of b-cell mass, and a dramatic amelioration of T1D. We further find that iPLA 2b inhibition markedly reduces immune responses. These observations provide strong evidence for contribution of iPLA2b-derived lipids to T1D development. Our on-going investigations reveal that activation of iPLA2b triggers molecular mechanisms that favor generation of pro -apoptotic/pro-inflammatory signals and these work in concert to promote T1D development. Our work was supported by the American Diabetes Association, NIH/NIDDK, and the Iacocca Family Foundation.