Kidney Protection by AMPK

该提案描述了一项为期5年的研究、培训和职业发展计划，旨在促进Dr。 潘从初级调查员过渡到独立调查员。她完成了内科住院医师和T32 贝勒的肾脏学研究奖学金。她于7月加入BCM，担任肾脏病学助理教授 2013年。该应用程序旨在利用成功调查人员的研究资源和专业知识 在BCM。潘博士创建了一个由高级调查人员组成的职业咨询委员会，致力于 指导年轻科学家，为她的研究和职业发展提供指导。大卫·谢赫博士- BCM的医学(肾脏病)教授哈马德将担任她的主要导师。他是由退伍军人管理局资助的 荣誉奖和NIH R01，是肾脏炎症、缺血/再灌注(I/R)肾损伤方面的专家，以及 锡钙素的抗氧化作用。她的联合顾问是：威廉·E·米奇医学博士，肌肉专家 新陈代谢；2)新陈代谢研究创新者强通博士；3)新陈代谢专家王力军博士 线粒体遗传学和功能；以及4)维贾伊·耶科尔，医学博士，胰岛素抵抗的成功研究者 还有糖尿病。潘博士的职业发展计划包括经常与她的导师会面，传授 增加科学知识，参加会议介绍她的研究成果。 急性肾损伤(AKI)很常见，并与发病率/死亡率增加有关，进展为 慢性肾脏疾病。然而，AKI的治疗选择仍然有限。ATP/营养耗竭和 氧化应激在发病机制中起着重要作用。我们的数据表明，锡钙素-1(STC1) 通过AMPK抑制ROS并对I/R肾损伤(一种缺血性AKI模型)产生抵抗 激活，优先是AMPK2亚型。此外，STC1还诱导线粒体长寿基因 SIRT3通过AMPK激活。SIRT3已被证明可以抑制ROS，而这一授权将测试中央 假设：STc1/AMPKα2/SIRT3是一条可诱导和适应性的能量感知通路，它抑制了 线粒体产生超氧化物并保护I/R肾损伤。利用体外低氧/复氧 损伤模型，Aim I将检测选择性地敲除AMPK2的siRNA是否减少STc1诱导的 细胞保护和SIRT3的表达。使用双突变体STC1Tg/AMPKα1 KO或STC1Tg/AMPKα2 KO 小鼠，Aim II将在体内研究STC1诱导的肾脏保护是否通过优先 AMPKsiRNA的激活2.利用SIRT3Tg和SIRT3KO小鼠以及体外过表达或α- 介导的SIRT3的敲除，AIM III将确定SIRT3的过度表达是否具有保护性 缺血性肾损伤。目的研究SIRT3在缺血性脑血管病中的作用。 Aki，以及性激素调节对SIRT3/AMPK表达的影响。我们的研究发现 STc1/AMPKα-2/SIRT3作为治疗缺血性急性心肌梗死的新靶点及其建议靶点 将表征并进一步确定SIRT3和AMPK2在肾脏保护中的作用。 BCM的研究环境是培养年轻人继续教育和发展的理想环境 内科医生调查员。潘博士将受益于出色的指导和强有力的机构支持。

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.