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

随函附上一份为期5年的指导培训计划的建议，以发展临床科学家的职业生涯， 儿科重症监护医学，研究儿童血管功能障碍的病理生理学。的 主要研究者是儿科和儿科重症监护医学委员会认证的医生， 目前是弗吉尼亚大学的助理教授。弗吉尼亚大学的资源， 该计划的理想包括多产的多学科科学家在亚硝基硫醇化学领域， 适应、血管生物学和细胞内信号传导。 这项拟议的研究将探索血管发育的机制， 这种疾病是由转录因子低氧诱导因子-1调节的。我们的初步数据 实验室已经表明，内源性亚硝基硫醇，S-亚硝基谷胱甘肽，激活缺氧诱导型 因子-1在常氧中的作用，PI 3-k/Akt通路的抑制剂阻止了这种激活。因此 这项研究的具体目标是：1）寻求辨别细胞外S- 亚硝基谷胱甘肽影响PI 3-k/Akt通路以及该通路如何激活缺氧诱导的 因子-1;和2）检查S-亚硝基谷胱甘肽是否通过巯基（S）-亚硝基化激活该级联反应 反应，独立的一氧化氮信号通过鸟苷酸环化酶。 本加斯顿博士，谁拥有在亚硝基硫醇化学领域的国际声誉将指导 候选人的科学发展，沿着博士丽莎帕尔默，研究副教授在 儿科和麻醉学，谁将作为一个密切的共同导师。帕尔默博士在 亚硝基硫醇化学和缺氧生物学。Kodi Ravichandran博士，免疫学教授， 细胞内信号传导领域的领导者，是候选人的早期导师，并将继续在关闭 顾问角色和候选人的研究监督。咨询委员会的其他成员也将 包括药理学主席JimGarrison博士和PI 3-激酶激活专家，以及Susan博士 凯利，儿科研究助理教授，具有机械分子生物学方面的专业知识， 肾梗阻这种环境是开展独立学术生涯的完美模式 候选人的具体目标。

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.