Kidney Protection by AMPK

AMPK 保护肾脏

• 批准号: 9240907
• 负责人: Jenny Szu-Chin Pan
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9240907
• 关键词: 5' -AMP-activated protein kinase; Acute Renal Failure with Renal Papillary Necrosis; Advisory Committees; Age; Animal Model; Antioxidants; Attenuated; Award; Caloric Restriction; Cells; Cessation of life; Chronic Kidney Failure; Complex; Continuing Education; Cytoprotection; Data; Development; Development Plans; Diabetes Mellitus; Doctor of Philosophy; Engineering; Environment; Estradiol; Estrone; Family; Fellowship; Female; Fostering; Funding; Gender; Generations; Genetic; Gonadal Steroid Hormones; Grant; Hypoxia; In Vitro; Inflammation; Injury; Insulin Resistance; Internal Medicine; Ischemia; Kidney; Kidney Failure; Knockout Mice; Knowledge; Lead; Longevity; Mediating; Medicine; Mentors; Metabolic; Mitochondria; Modeling; Morbidity - disease rate; Mus; Nephrology; Nutrient; Organ; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phenotype; Physicians; Play; Population; Predisposition; Production; Protein Isoforms; Protein Kinase; Proteins; Recombinants; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Research Personnel; Research Training; Residencies; Resistance; Resources; Role; STC1 gene; Scientist; Serum; Sex Characteristics; Sirtuins; Small Interfering RNA; Stanolone; Superoxides; Testing; Testosterone; Therapeutic; Transferase; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; Veterans; Work; age effect; anti aging; career; career development; design; experimental study; gender difference; hormone regulation; in vivo; inhibitor/antagonist; innovation; knock-down; longevity gene; male; meetings; member; mortality; muscle metabolism; mutant; new therapeutic target; novel therapeutics; overexpression; oxidant stress; professor; renal ischemia; research and development; response; response to injury; sensor; sexual dimorphism; symposium

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.

该建议描述了一项为期5年的研究培训和职业发展计划，旨在促进博士。 潘从初级调查员过渡到独立调查员。她完成了内科住所和T32 肾脏研究奖学金在贝勒。她于7月加入BCM担任肾脏科助理教授 2013年。该申请是为了利用成功研究人员的研究资源和专业知识 在BCM。 Pan博士成立了一个职业咨询委员会，由专门研究的高级调查员组成 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的医学教授（肾脏病）将担任她的主要导师。他由VA资助 优异奖和NIH R01，是肾脏注射，缺血/再灌注（I/R）肾脏损伤的专家 Stanniocalcins的抗氧化作用。她的共同顾问是：1）肌肉专家威廉·米奇（William E. Mitch） 代谢; 2）Qiang Tong，PhD，Sirtuin Research的创新者； 3）Lee-Jun Wong博士，专家 线粒体遗传学和功能； 4）医学博士Vijay Yechoor，胰岛素抵抗的成功研究者 和糖尿病。 Pan博士的职业发展计划包括与她的导师会面，教学法 增加科学知识，并参加会议以展示她的研究。 急性肾脏损伤（AKI）很常见，并且与发病率/死亡率的增加有关 慢性肾脏疾病。但是，AKI的治疗选择仍然有限。 ATP/营养部署和 氧化应激在发病机理中起重要作用。我们的数据表明Stanniocalcin-1（STC1） 通过AMPK抑制ROS并赋予对I/R肾损伤（缺血性AKI的模型）的抵抗力 激活优先是AMPK2同工型。此外，STC1诱导线粒体寿命基因 SIRT3通过AMPK激活。 SIRT3已显示可抑制ROS，该赠款将测试中央 假设：STC1/AMPKα2/SIRT3是一种诱导且适应性的能量传感途径 线粒体超氧化物的产生并免受I/R肾脏损伤。使用体外缺氧/重氧 伤害模型，目的我将检查AMPK2的选择性siRNA敲低是否会减小STC1诱导的 细胞保护和SIRT3表达。使用双突变体STC1 TG/AMPKα1KO或STC1 TG/AMPKα2KO 小鼠，AIM II将在体内检查STC1诱导的肾脏保护是否是通过首选介导的 AMPKα2的激活。使用SIRT3 TG和SIRT3 KO小鼠，以及体外过表达或siRNA- SIRT3的介导敲低，AIM III将确定SIRT3过表达是否受到保护 缺血性肾脏受伤。 AIM IV将检查SIRT3在观察到的性二态性中的作用 AKI，以及性别同性调制对SIRT3/AMPK表达的影响。我们的研究确定 STC1/AMPKα2/SIRT3作为缺血性AKI治疗的新型治疗靶标 将描述并进一步定义SIRT3和AMPK2在肾脏保护中的作用。 BCM的研究环境非常适合促进年轻的持续教育和发展 医师调查员。 Pan博士将受益于出色的心理和强大的机构支持。