GSNO regulates HIF-1alpha by activation of PI 3-k/Akt

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Enclosed is a proposal for a 5 year mentored training program to develop a clinician-scientist career in Pediatric Critical Care Medicine, studying the pathophysiology of vascular dysfunction in children. The principle investigator is a Board-certified physician in Pediatrics, and Pediatric Critical Care Medicine, and is currently an Assistant Professor at the University of Virginia. Resources at University of Virginia that make this program ideal include prolific multidisciplinary scientists in the areas of Nitrosothiol Chemistry, Hypoxic Adaptation, Vascular Biology and Intracellular Signaling. This proposed research will explore the mechanisms through which the development of vascular disease is regulated by the transcription factor, Hypoxia Inducible Factor-1. Preliminary data in our laboratory has shown that the endogenous nitrosothiol, S-nitrosoglutathione, activates Hypoxia Inducible Factor-1 in normoxia, and that inhibitors of the PI 3-k/Akt pathway prevent this activation. Therefore, the specific aims of this proposed research will: 1) seek to discern the mechanism by which extracellular S- nitrosoglutathione influences the PI 3-k/Akt pathway and how this pathway activates Hypoxia Inducible Factor-1; and 2) examine whether S-nitrosoglutathione activates this cascade through a thiol(S)-nitrosylation reaction, independent of nitric oxide signaling through guanylate cyclase. Dr. Ben Gaston, who has an international reputation in the field of nitrosothiol chemistry will mentor the candidate's scientific development, along with Dr. Lisa Palmer, an Associate Professor of Research in Pediatrics and Anesthesiology, who will serve as a close co-mentor. Dr. Palmer is well-known in the field of nitrosthiol chemisty and the biology of hypoxia. Dr. Kodi Ravichandran, a Professor of Immunology and a leader in the field of intracellular signaling, was the candidate's early mentor and will continue in a close advisory role and oversight of the candidate's research. Other members of the advisory committee will also include Dr. Jim Garrison, chairman of Pharmacology, and an expert in PI 3-kinase activation, and Dr. Susan Kiley, Assistant Professor of Research in Pediatrics, with expertise in the molecular biology of mechanical renal obstruction. This environment is the perfect model in which to launch an independent academic career with the candidate's specified goals.