Kidney Protection by AMPK

本提案描述了一个为期5年的研究培训和职业发展计划，旨在促进博士。 潘从初级调查员到独立调查员的转变。她完成了内科住院医师和T32 贝勒大学肾脏病学研究奖学金。她于7月加入哈佛大学，担任肾脏病学助理教授。 2013.该应用程序旨在利用研究资源和成功的调查人员的专业知识 在……潘博士成立了一个由资深研究人员组成的职业咨询委员会， 指导年轻科学家为她的研究和职业发展提供指导。大卫·谢赫医生- 哈马德，医学教授（肾脏病学）在休斯敦，将担任她的主要导师。他由退伍军人事务部资助 优异奖和NIH R 01，是肾脏炎症、缺血/再灌注（I/R）肾损伤和 锡钙素的抗氧化作用。她的共同顾问是：1）威廉E。米奇，医学博士，肌肉专家 2）Qiang Tong博士，sirtuin研究的创新者; 3）Lee-Jun Wong博士， 线粒体遗传学和功能;以及4）Vijay Yechoor，医学博士，胰岛素抵抗的成功研究者 和糖尿病潘博士的职业发展计划包括经常与导师会面， 增加科学知识，并参加会议，介绍她的研究。 急性肾损伤（阿基）是常见的，并且与发病率/死亡率增加和进展至急性肾损伤相关。 慢性肾脏疾病。然而，阿基的治疗选择仍然有限。ATP/营养素消耗和 氧化应激在其发病机制中起重要作用。我们的数据表明，斯钙素-1（STC 1） 通过AMPK抑制ROS并赋予对I/R肾损伤（缺血性阿基的模型）的抗性 激活，优选AMPK β 2同种型。此外，STC 1诱导线粒体长寿基因 SIRT 3通过AMPK激活。SIRT 3已被证明可以抑制ROS，这项拨款将测试中央 假设：STC 1/AMPKα2/SIRT 3是一种可诱导的适应性能量感知通路，抑制 线粒体超氧化物产生和保护I/R肾损伤。利用体外缺氧/复氧 损伤模型，目的I将检查AMPK β 2的选择性siRNA敲低是否减少STC 1诱导的损伤。 细胞保护和SIRT 3表达。使用双突变型STC 1 Tg/AMPKα1 KO或STC 1 Tg/AMPKα2 KO Aim II将在小鼠体内检测STC 1诱导的肾保护作用是否通过优先的 AMPKα2的激活。使用SIRT 3 Tg和SIRT 3 KO小鼠，以及体外过表达或siRNA- 通过SIRT 3介导的敲低，Aim III将确定SIRT 3过表达是否对SIRT 3的表达具有保护作用， 缺血性肾损伤目的IV将研究SIRT 3在缺血性脑血管病中观察到的性二型性中的作用。 阿基，以及性激素调节对SIRT 3/AMPK表达的影响。我们的研究发现 STC 1/AMPKα2/SIRT 3作为治疗缺血性阿基的新靶点，以及提出的目标 将表征并进一步确定SIRT 3和AMPK β 2在肾脏保护中的作用。 研究环境在斯坦福大学是理想的促进继续教育和发展的年轻人 医生调查员。潘博士将受益于出色的指导和强大的机构支持。

This proposal describes a 5-year research training and career development plan designed to facilitate Dr. Pan’s transition from junior to independent investigator. She completed Internal Medicine residency and a T32 Nephrology Research Fellowship at Baylor. She joined BCM as an Assistant Professor in Nephrology in July 2013. The application is devised to make use of research resources and expertise of successful investigators at BCM. Dr. Pan has created a Career Advisory Committee consisting of senior investigators dedicated to mentoring young scientists to provide guidance with her research and career development. Dr. David Sheikh- Hamad, Professor of Medicine (Nephrology) at BCM, will serve as her primary mentor. He is funded by a VA Merit award and NIH R01 and is an expert in renal inflammation, ischemia/reperfusion (I/R) kidney injury, and the anti-oxidant actions of stanniocalcins. Her co-advisors are: 1) William E. Mitch, MD, an expert in muscle metabolism; 2) Qiang Tong, PhD, an innovator in sirtuin research; 3) Lee-Jun Wong, PhD, an expert in mitochondrial genetics and function; and 4) Vijay Yechoor, MD, a successful investigator in insulin resistance and diabetes. Dr. Pan’s career development plan includes frequent meetings with her mentors, didactics to increase scientific knowledge, and attending conferences to present her research. Acute kidney injury (AKI) is common and associated with increased morbidity/mortality, and progression to chronic kidney disease. However, the therapeutic options for AKI remain limited. ATP/nutrient depletion and oxidative stress play important roles in the pathogenesis. Our data suggest that stanniocalcin-1 (STC1) suppresses ROS and confers resistance to I/R kidney injury (a model for ischemic AKI) through AMPK activation, preferentially the AMPK2 isoform. Moreover, STC1 induces the mitochondrial longevity gene SIRT3 via AMPK activation. SIRT3 has been shown to suppress ROS, and this grant will test the Central Hypothesis that: STC1/AMPKα2/SIRT3 is an inducible and adaptive energy sensing pathway that suppresses mitochondrial superoxide production and protects from I/R kidney injury. Using in vitro hypoxia/reoxygenation injury model, Aim I will examine whether selective siRNA knockdown of AMPK2 diminishes STC1-induced cytoprotection and SIRT3 expression. Using double mutant STC1 Tg/AMPKα1 KO or STC1 Tg/AMPKα2 KO mice, Aim II will examine in vivo whether STC1-induced renoprotection is mediated through preferential activation of AMPKα2. Using SIRT3 Tg and SIRT3 KO mice, as well as in vitro overexpression or siRNA- mediated knockdown of SIRT3, Aim III will determine whether SIRT3 overexpression is protective from ischemic kidney injury. Aim IV will examine the role of SIRT3 in the observed sexual dimorphism in ischemic AKI, and the effect of sex hormone modulation on SIRT3/AMPK expression. Our studies identify STC1/AMPKα2/SIRT3 as novel therapeutic targets for the treatment of ischemic AKI, and the proposed aims will characterize and further define the role of SIRT3 and AMPK2 in kidney protection. The research environment at BCM is ideal for fostering the continued education and development of young physician investigators. Dr. Pan will benefit from outstanding mentoring and strong institutional support.