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October 2011 Researcher of the Month - Vivek Rai, PhD

Vivek Rai, PhD

Research Studies in the Diabetes Research Program

The immunoglobulin superfamily molecule RAGE (receptor for advanced glycation end product) transduces the effects of multiple ligands, including AGEs (advanced glycation end products), S100/calgranulins, high-mobility group box-1, amyloid-beta peptide, and beta-sheet fibrils. In diabetes, hyperglycemia likely stimulates the initial burst of production of ligands that interact with RAGE and activate signaling mechanisms. Consequently, increased generation of proinflammatory and prothrombotic molecules and reactive oxygen species trigger further cycles of oxidative stress via RAGE, thus setting the stage for augmented damage to diabetic tissues in the face of further insults. Many of the ligand families of RAGE have been identified in atherosclerotic plaques and in the infarcted heart.

Our work suggests that RAGE-dependent acceleration of atherosclerosis in ApoE-null mice is dependent on the action of the ROCK1 branch of the transforming growth factor-beta pathway. In another study, the solution structure of a CEL-containing peptide-RAGE V domain complex reveals that the arboxyethyl moiety fits inside a positively charged cavity of the V domain. Peptide backbone atoms make specific contacts with the V domain. The geometry of the bound CEL peptide is compatible with many CML (CEL)-modified sites found in plasma proteins. The structure explains how such patterned ligands as CML (CEL)-proteins bind to RAGE and contribute to RAGE signaling. Further, we discovered a novel ligand, for RAGE in vascular signaling and tumorigenesis.

These findings identify novel roles for RAGE as a conduit for ligand signaling and indicate that therapeutic strategies to modify the pathological actions of LPA in vascular disease and tumorigenesis should include targeting the interaction of LPA with RAGE.

Abstracts and meetings attended
Vivek Rai, Fatouma Touré, Seth Chitayat, Renjun Pei, Yan Lu, Qing Li, Rosa Rosario, Zhengbin Zhu, Wu Qu, Fei Song, Ravichandran Ramasamy, Walter J. Chazin and Ann Marie Schmidt. Lysophosphatidic Acid Mediates Vascular Signaling via an Immunoglobulin Superfamily Receptor. Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB), Chicago, IL Apr 28-31, 2011.

Vivek Rai, Andres Maldonado, Shi-Fang Yan, Ann Marie Schmidt* and Alexander Shekhtman. Solution structure and amino acid residues of C-terminal RAGE (ctRAGE) involved in binding to Dia-1 FH1 and its signaling. Experimental Biology (FASEB), Washington DC, April 9-13, 2011. (Oral Presentation)

Yared Tekabe, Vivek Rai, Joane Luma, Ann Marie Schmidt, Lynne L Johnson. RAGE directed Imaging of Tumor 2010 World Molecular Imaging Congress (WMIC), Kyoto, Japan Sept 8-11, 2010.

V. Rai, D. Bu, X. Shen, R. Rosario, Y. Lu, S. Yan, R. Friedman, AM Schmidt. RAGE Initiates and Accelerates Early Atherosclerosis in Diabetic ApoE Null Mice in Part via ROCK1 Activation in Smooth Muscle Cells. 49th American Society for Cell Biology Annual Meeting (ASCB), San Diago, CA, December 5-9, 2009.

Rai V. and Datta K. Hyaluronan Binding Protein 1 HABP1/p32/gC1qR Upregulation and Nuclear Translocation is Associated with Muscle Differentiation., 47th American Society for Cell Biology Annual Meeting (ASCB), Washington, DC, on December 1-5, 2007.

Awards
Robert S. Holzman Award, 2011 for Excellence in Research for the outstanding investigation at Department of Medicine, NYUMC, New York.

Selected Publications
Jing Xue*, Vivek Rai*, Sergey Frolov, Jingjing Xie, Sergey Reverdatto, David S. Burz, Ann Marie Schmidt, Ralf Hoffman, Alexander Shekhtman. Structural mechanism of the advanced glycated end products (AGEs) recognition by their receptor RAGE. Structure, 2011; 19(5):722-32. (*Equal First Author)
Reviewed in http://www.sciencedirect.com/science/article/pii/S096921261100147X

Reiniger N, Lau K, McCalla D, Eby B, Cheng B, Lu Y, Qu W, Quadri N, Ananthakrishnan R, Furmansky M, Rosario R, Song F, Rai V, Weinberg A, Friedman R, Ramasamy R, D'Agati V, Schmidt AM. Deletion of the Receptor for Advanced Glycation Endproducts Reduces Glomerulosclerosis and Preserves Renal Function in the Diabetic OVE26 Mouse. Diabetes. 2010; 59(8):2043-54.

Bu DX*, Rai V* ( *Equal First Author), Shen X, Rosario R, Lu Y, D'Agati V, Yan SF, Friedman RA, Nuglozeh E, Schmidt AM. Activation of the ROCK1 Branch of the Transforming Growth Factor-β Pathway Contributes to RAGE-Dependent Acceleration of Atherosclerosis in Diabetic ApoE Null Mice. Circulation Research. 2010; 106(6):1040-51.

Yadav G, Prasad RL, Jha BK, Rai V, Bhakuni V, Datta K., Evidence for inhibitory interaction of hyaluronan binding protein 1 (HABP1/p32/gC1qR) with S.pneumoniae hyaluronidase J. Biol. Chem. 2009; 284(6):3897-905.

Future Plans
The long term goal of my research is to understand the molecular mechanisms of Type 1 diabetes via RAGE receptor and the identification of key components functioning in insulin action on glucose metabolism for the efforts of preventing and treating type 2 diabetes mellitus.