Kidney Protection by AMPK

AMPK 保护肾脏

• 批准号: 10265338
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265338
• 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; Injury to Kidney; 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 Depletion; Organ; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phenotype; Physicians; Play; 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 Differences; Sirtuins; Small Interfering RNA; Stanolone; Superoxides; Testing; Testosterone; Therapeutic; Transferase; Transgenic Mice; Transgenic Organisms; United States National Institutes of Health; 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; military veteran; 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.

该提案描述了一项为期 5 年的研究培训和职业发展计划，旨在促进 Dr. Pan 从初级研究员转变为独立研究员，她完成了内科住院医师培训并取得了 T32 资格。 她于 7 月加入 BCM，担任贝勒肾病学研究助理教授。 2013. 该应用程序旨在利用成功研究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研究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。 BCM 医学（肾病学）教授 Hamad 将担任她的主要导师。他由 VA 资助。 优异奖和 NIH R01，是肾脏炎症、缺血/再灌注 (I/R) 肾损伤和 她的共同顾问是：1) William E. Mitch，医学博士，肌肉专家。 2) 童强博士，sirtuin 研究的创新者；3) Lee-Jun Wong 博士，代谢领域专家； 线粒体遗传学和功能；4) Vijay Yechoor，医学博士，胰岛素抵抗领域的成功研究者 潘博士的职业发展计划包括经常与她的导师会面、进行教学。 增加科学知识，并参加会议展示她的研究。 急性肾损伤 (AKI) 很常见，与发病率/死亡率增加以及进展为相关 然而，AKI 的治疗选择仍然有限。 我们的数据表明，氧化应激在发病机制中发挥重要作用。 通过 AMPK 抑制 ROS 并赋予对 I/R 肾损伤（缺血性 AKI 模型）的抵抗力 此外，STC1 还诱导线粒体长寿基因。 SIRT3 通过 AMPK 激活已被证明可以抑制 ROS，这项资助将测试 Central。 假设：STC1/AMPKα2/SIRT3 是一种可诱导的、适应性的能量传感通路，可抑制 使用体外缺氧/复氧来产生线粒体超氧化物并防止 I/R 肾损伤。 损伤模型，目的我将检查选择性 siRNA 敲低 AMPKα2 是否会减少 STC1 诱导的损伤 使用双突变体 STC1 Tg/AMPKα1 KO 或 STC1 Tg/AMPKα2 KO 进行细胞保护和 SIRT3 表达。 Aim II 将在小鼠体内检查 STC1 诱导的肾脏保护是否是通过优先介导的 使用 SIRT3 Tg 和 SIRT3 KO 小鼠以及体外过表达或 siRNA 激活 AMPKα2。 介导的 SIRT3 敲低，目标 III 将确定 SIRT3 过表达是否具有保护作用 目标 IV 将检查 SIRT3 在缺血性肾损伤中观察到的性别二态性的作用。 我们的研究确定了 AKI 以及性激素调节对 SIRT3/AMPK 表达的影响。 STC1/AMPKα2/SIRT3 作为治疗缺血性 AKI 的新治疗靶点及其提出的目标 将表征并进一步定义 SIRT3 和 AMPKα2 在肾脏保护中的作用。 BCM 的研究环境非常适合促进年轻人的继续教育和发展 潘博士将受益于出色的指导和强有力的机构支持。

项目成果

Mineral and Bone Disorders After Kidney Transplantation.

肾移植后的矿物质和骨骼疾病。

• 发表时间: 2018
• 作者: Vangala, Chandan;Pan, Jenny;Cotton, Ronald T;Ramanathan, Venkat
• 通讯作者: Ramanathan, Venkat

Potential Mechanisms Involved in Chronic Kidney Disease of Unclear Etiology.

病因不明的慢性肾脏病的潜在机制。

• 发表时间: 2022-09
• 作者: Holliday Jr, Michael W;Li, Qingtian;Bustamante, Edlyn G;Niu, Jingbo;Huang, Luping;Espina, Ilse M;Dominguez, Jose R;Truong, Luan;Murray, Kristy O;Fan, Lei;Anumudu, Samaya J;Shah, Maulin;Fischer, Rebecca S B;Vangala, Chandan;Mandayam, Sreedhar
• 通讯作者: Mandayam, Sreedhar

Trends in the Causes of Death among Kidney Transplant Recipients in the United States (1996-2014).

美国肾移植受者的死因趋势（1996-2014 年）。

• 发表时间: 2018
• 影响因子: 4.2
• 作者: Awan, Ahmed A;Niu, Jingbo;Pan, Jenny S;Erickson, Kevin F;Mandayam, Sreedhar;Winkelmayer, Wolfgang C;Navaneethan, Sankar D;Ramanathan, Venkat
• 通讯作者: Ramanathan, Venkat