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

随函附上一份5年指导培训计划的建议书，以发展临床医生-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。这个 首席调查员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使 这一计划理想包括多学科的科学家在亚硝硫醇化学，缺氧 适应，血管生物学和细胞内信号转导。 这项拟议的研究将探索血管发育的机制 疾病受转录因子低氧诱导因子-1的调控。我们的初步数据 实验室研究表明，内源性亚硫醇S-亚硝基谷胱甘肽可激活低氧诱导 PI3-k/Akt通路的抑制剂阻止了这种激活。因此， 这项拟议研究的具体目的将：1)试图弄清细胞外S- 亚硝基谷胱甘肽对PI3-k/Akt通路的影响及该通路如何激活低氧诱导 因子-1；和2)检测S-亚硝基谷胱甘肽是否通过硫醇(S)-亚硝化激活这一级联反应 反应，不依赖于通过鸟苷环化酶传递的一氧化氮信号。 在亚硝硫醇化学领域享有国际声誉的Ben Gaston博士将指导 候选人的科学发展，与丽莎·帕尔默博士一起，她是 儿科学和麻醉学，谁将担任密切合作导师。帕尔默博士在 亚硝硫醇化学与缺氧生物学。Kodi Ravichandran博士，免疫学教授和 细胞内信号领域的领导者，是候选人的早期导师，并将在结束时继续 对候选人的研究起到咨询和监督作用。咨询委员会的其他成员也将 包括药理学主席、PI3K激活专家吉姆·加里森博士和苏珊博士 Kiley，儿科学研究助理教授，拥有机械分子生物学方面的专业知识 肾梗阻。这种环境是开始独立学术生涯的完美模式。 有候选人指定的目标。

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.