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年的指导培训计划的建议，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。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使该计划成为理想选择，包括亚硝基硫醇化学，低血糖适应，血管生物学和细胞内信号传导领域的多产多学科科学家。 这项研究将探讨血管疾病的发展是通过转录因子，缺氧诱导因子-1调节的机制。我们实验室的初步数据表明，内源性亚硝基硫醇，S-亚硝基谷胱甘肽，激活缺氧诱导因子-1在常氧，和PI 3-k/Akt途径的抑制剂防止这种激活。因此，本研究的具体目的是：1）试图辨别细胞外S-亚硝基谷胱甘肽影响PI 3-k/Akt通路的机制以及该通路如何激活缺氧诱导因子-1; 2）检查S-亚硝基谷胱甘肽是否通过巯基（S）-亚硝基化反应激活该级联反应，而不依赖于通过鸟苷酸环化酶的一氧化氮信号传导。 博士本加斯顿，谁拥有在亚硝基硫醇化学领域的国际声誉将导师候选人的科学发展，沿着与丽莎帕尔默博士，在儿科和麻醉学研究的副教授，谁将担任密切的共同导师。Palmer博士在亚硝基硫醇化学和缺氧生物学领域非常知名。Kodi Ravichandran博士是免疫学教授，也是细胞内信号传导领域的领导者，他是候选人的早期导师，并将继续担任密切的顾问角色，并监督候选人的研究。咨询委员会的其他成员还包括药理学主席Jim Garrison博士和PI 3激酶激活专家，以及儿科研究助理教授Susan Kiley博士，具有机械性肾梗阻分子生物学方面的专业知识。这种环境是一个完美的模式，在其中启动一个独立的学术生涯与候选人的指定目标。

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.