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.

该提案描述了一个5年的研究培训和职业发展计划，旨在促进博士。