Rama Natarajan, Ph.D, F.A.H.A, F.A.S.N. Research
The major focus of our research is to determine the cellular and molecular mechanisms that play key roles in the development of diabetic vascular complications. We use genomic, transcriptomic and epigenomic approaches in cell culture, animal and clinical models to examine our hypothesis that accelerated vascular complications result from enhanced vascular and renal cell growth, and also monocyte activation due to altered expression of inflammatory cytokines, chemokines and lipids under diabetic conditions.
We are actively evaluating molecular mechanisms involved in the expression of pathological genes under diabetic conditions and in promoting metabolic memory. We have demonstrated the role of specific chromatin histone posttranslational modifications in the epigenetic regulation of inflammatory genes. We use epigenomic profiling approaches to map histone modifications, DNA methylation and binding of chromatin factors at diabetes-regulated genes with techniques such as Chromatin immunoprecipitation (ChIP) assays, ChIP-linked to microarrays, and ChIP-Sequencing. We have uncovered key epigenetic alterations under diabetic conditions in vitro, in vivo in diabetic mice, and in cells from diabetic patients, and shown relevance to the phenomenon of metabolic memory.
Another active area is the evaluation of specific microRNAs in regulating the expression of inflammatory and fibrotic genes under diabetic conditions. We are examining various mechanisms of microRNA regulation, performing expression profiling using RNA-sequencing, and studying how key microRNAs co-operate with each other in a circuit to amplify the effects of growth factors under diabetic conditions. To test the functional significance in the kidney, we are generating microRNA knockout mice and also evaluating novel modified inhibitors of specific microRNAs (antagomirs) on the progression of diabetic kidney disease in mouse models.