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

描述(由申请人提供)：随函附上一份为期5年的指导性培训计划的建议书，以发展儿科重症监护医学的临床医生-科学家职业生涯，研究儿童血管功能障碍的病理生理学。首席研究员是儿科学和儿科重症监护医学委员会认证的内科医生，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项目成为理想的项目，包括在亚硝硫醇化学、低氧适应、血管生物学和细胞内信号转导领域的多学科科学家。 这项拟议的研究将探索转录因子低氧诱导因子-1调控血管疾病发展的机制。我们实验室的初步数据表明，内源性亚硫醇S-亚硝基谷胱甘肽能激活常氧条件下的缺氧诱导因子-1，而PI 3-k/Akt通路的抑制剂可以阻止这种激活。因此，本研究的具体目的是：1)研究细胞外S-亚硝基-谷胱甘肽影响PI3-k/Akt通路的机制，以及该通路如何激活缺氧诱导因子-1；2)检测S-亚硝基-谷胱甘肽是否通过硫醇(S)-亚硝化反应激活这一级联反应，而不依赖于一氧化氮通过鸟苷环化酶传递的信号。 在亚硝硫醇化学领域享有国际声誉的本·加斯顿博士将指导候选人的科学发展，儿科学和麻醉学研究副教授丽莎·帕尔默博士将担任密切的共同导师。帕尔默博士在亚硝硫醇化学和缺氧生物学领域很有名气。Kodi Ravichandran博士是免疫学教授，也是细胞内信号领域的领导者，他是候选人的早期导师，并将继续担任候选人研究的密切顾问和监督角色。咨询委员会的其他成员还将包括药理学主席、PI 3-激酶激活专家吉姆·加里森博士，以及在机械性肾梗阻的分子生物学方面具有专长的儿科学研究助理教授苏珊·基利博士。这种环境是开启具有特定目标的独立学术生涯的完美模式。

DESCRIPTION (provided by applicant): 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 nitrosothiol chemistry 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.