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 Genomics, Epigenomics and Proteomics approaches in cell culture models, animal models of diabetes as well as human blood cells to examine our hypothesis that accelerated diabetic vascular and renal complications result from enhanced vascular smooth muscle and renal mesangial cell growth, and also monocyte activation. These in turn are the consequences of altered expression and actions of inflammatory cytokines, chemokines and lipids under diabetic conditions.

Our results suggest that high glucose (HG) and advanced glycation end products (AGEs) might be directly linked to accelerated vascular complications by increasing inflammatory and growth promoting genes in vascular smooth muscle cells (VSMC), renal cells and monocytes. We have uncovered key pathways and molecular signals, including as NF-kB, that integrate and amplify the effects of HG or AGEs on inflammatory genes and demonstrated that the diabetic phenotype can be attenuated by blocking these pathways with methods such as RNA interference. We are also determining the in vivo functional significance in animal models of diabetes and atherosclerosis. These data will also be used in the City of Hope islet transplantation program to follow patients before and after transplantation.

We are also evaluating the transcriptional and post-transcriptional mechanisms of regulation of inflammatory genes by HG, AGEs and growth factors in monocytes, renal and vascular cells. We are examining the profile of chromatin factor binding to key diabetes-regulated genes by using state-of-the-art techniques such as Chromatin immunoprecipitation (ChIP) assays, ChIP-on-chip, microarray and Genome-wide Location Analyses. Our studies have uncovered novel “epigenetic” alterations and chromatin remodeling events under diabetic conditions in vitro, in vivo in diabetic mice and also in cells obtained from diabetic patients. Alongside, we are actively examining the specific role of histone modifications and also microRNAs in gene regulation under diabetic conditions.

Another active area of research in my laboratory is the evaluation of mechanisms of action of oxidized lipids since dyslipidemia is a major risk factor for diabetic complications. I have contributed extensively to this area by examining the actions of oxidized lipid products, including those of the 12/15-lipoxygenase (12/15-LO) pathway of arachidonate metabolism. We are  testing the functional significance of 12/15-LO by using mouse models of 12/15-LO ablation or overexpression, as well as novel modified siRNAs to block these pathologic pathways in vitro and in vivo. We are also using these techniques to study the roles of key microRNAs and fibrotic genes that mediate nephropathy, a major renal complication associated with diabetes.
Overall, our studies combine molecular techniques with cellular and animal models to determine the mechanisms by which diabetic stimuli affect target cells. These ventures may lead to novel therapeutic modalities to reduce or prevent the serious complications associated with diabetes.

Rama Natarajan, Ph..D., FAHA, FASN
Professor
626-256-HOPE (4673), ext. 62289

Marpadga A. Reddy, Ph.D.
Assistant Research Scientist
626-256-HOPE (4673), ext. 63671

Feng Miao, Ph.D.
Assistant Research Scientist
626-256-HOPE (4673), ext. 65575

Mitsuo Kato, Ph.D.
Senior Research Fellow
626-256-HOPE (4673), ext. 63996

Ali Ehsani
Research Fellow
626-256-HOPE (4673), ext. 64690

Laura Arce, Ph.D.
Research Fellow
626-256-HOPE (4673), ext. 61482

Guangdong Sun, M.D.
Research Fellow
626-256-HOPE (4673), ext. 65817

Jehyun Park, Ph.D.
Research Fellow
626-256-HOPE (4673), ext. 65823

Yan Li, M. S.
Graduate Student
626-256-HOPE (4673), ext. 65835

Louisa Villeneuve, B.S.
Graduate Student
626-256-HOPE (4673), ext. 64809

Sumanth Putta, B.V.Sc., M.S.
Graduate Student
626-256-HOPE (4673), ext. 63457

Linda Lanting, B.S.
Research Associate
626-256-HOPE (4673), ext. 64692

Mei Wang, M.S.
Research Associate
626-256-HOPE (4673), ext. 64676

Lingxiao Zhang, M.S.
Research Associate
626-256-HOPE (4673), ext. 65571

Nancy (Zhuo) Chen
Bioinformatics Specialist
656-256-HOPE (4673), ext. 65058