Mitochondrial dysfunction, oxidative stress, and surgical acute kidney injury

线粒体功能障碍、氧化应激和手术急性肾损伤

• 批准号: 8704361
• 负责人: Frederic Tremaine Billings
• 金额: $ 17.88万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704361
• 关键词: Academic Medical Centers; Acute; Acute Renal Failure with Renal Papillary Necrosis; Adverse effects; Anesthesiology; Animal Model; Antioxidants; Applications Grants; Award; Brain; Cardiac; Cardiac Surgery procedures; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chronic Kidney Failure; Clinic; Clinical; Clinical Pharmacology; Clinical Research; Clinical Trials Design; Conduct Clinical Trials; Consensus; DNA; DNA copy number; Data; Development; Development Plans; Diagnosis; Dialysis procedure; Dose; Double-Blind Method; Elements; Experimental Models; F2-Isoprostanes; Functional disorder; Funding; Future; Generations; Genetic Transcription; Goals; Grant; Heart failure; Hospitalization; Hospitals; Human; Incidence; Infection; Inflammatory; Injury; Injury to Kidney; Intensive Care Units; Investments; Ischemia; Junior Physician; Kidney; Kidney Diseases; Laboratories; Lead; Leukocytes; Lipids; Manuscripts; Measurement; Measures; Membrane Potentials; Mentors; Mentorship; Mitochondria; Mitochondrial DNA; Modeling; Morbidity - disease rate; Nitric Oxide; Nursing Research; Operating Rooms; Operative Surgical Procedures; Organ; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Pathway; Paper; Patients; Pattern; Performance; Perioperative; Peroxisome Proliferator-Activated Receptors; Physicians; Pilot Projects; Placebo Control; Placebos; Plasma; Postoperative Period; Preparation; Process; Proteins; Publishing; Pyruvate; Randomized; Randomized Clinical Trials; Reactive Oxygen Species; Recovery; Renal Replacement Therapy; Reperfusion Therapy; Research; Research Infrastructure; Research Personnel; Rodent; Sample Size; Schedule; Scientist; Secondary to; Staging; Structure; Study Subject; Techniques; Testing; Time; Toxin; Training; Translational Research; Ubiquinone Q2; Urine; Writing; atorvastatin; base; career; career development; design; experience; improved; meetings; mitochondrial dysfunction; multidisciplinary; professor; prospective; renal ischemia; response; skills; success; tool; treatment strategy

DESCRIPTION (provided by applicant): The candidate is an assistant professor of anesthesiology conducting translational research that tests mechanisms of acute kidney injury (AKI) following cardiac surgery. His immediate career goals are to 1) Test the hypothesis that mitochondrial dysfunction contributes to oxidative and AKI following cardiac surgery (see Specific Aims) and 2) Gain the skills and experiences required to become an independent investigator conducting clinical trials that test therapy for and mechanisms of surgery-induced AKI. His long-term career goals are to 1) Improve his capacity to develop and rigorously test hypotheses that decipher mechanisms of peri-operative organ dysfunction based on markers of pathophysiologic processes and 2) Establish, lead, and maintain funding for a multidisciplinary team that can test and develop new strategies to reduce acute organ dysfunction in patients undergoing surgery. The candidate, his mentor, and his mentorship committee have developed a comprehensive career development plan to meet these goals. The key elements of this plan are structured training in the pathophysiology of acute oxidant injury, mitochondrial dysfunction, and AKI, training in techniques relevant to hypothesis-testing clinical trial design and performance, structured mentorship from diverse physician-scientists with focus on scientific acumen development, and scheduled manuscript writing, presentation building, and grant preparation. He has published two papers on experimental models of AKI and three papers on the inflammatory/pro-oxidant response to surgery and therapy for AKI in humans. During the grant award period, the candidate will test the hypotheses that 1) Mitochondrial dysfunction is associated with oxidative stress during cardiac surgery and predicts AKI following cardiac surgery (Aim 1) and that 2) Treatment with a mitochondrial-targeted antioxidant, ubiquinone- 10, reduces mitochondrial dysfunction and oxidative stress in patients undergoing cardiac surgery (Aim 2). The candidate has recently shown that intraoperative concentrations of plasma and urine markers of oxidant injury (F2-isoprostanes and isofurans) predict the development of postoperative AKI. The pattern of F2- isoprostane and isofuran expression observed may be explained by mitochondrial dysfunction. In other preliminary studies, leukocyte mitochondrial DNA (mtDNA) coy number was significantly lower in cardiac surgery patients that developed AKI, intraoperative arterial lactate:pyruvate ratios correlated with postoperative urine concentrations of isofurans, and ubiquinone-10 reduced isofuran concentrations in chronic kidney disease patients. To accomplish Aim 1, the candidate will measure and compare preoperative, intraoperative, and postoperative plasma and urine concentrations of F2-isoprostanes and isofurans, markers of mitochondrial function (mitochondria redox potential, peroxisome proliferator-activated receptor ¿ coactivator 1-¿ (PGC-1¿) RNA expression, and mtDNA copy number from isolated leukocytes and arterial lactate:pyruvate ratios), and clinical AKI (defined using AKIN staging consensus criteria for AKI diagnosis) in 150 subjects who complete the Statin AKI Cardiac Surgery Randomized Clinical Trial, a trial testing the hypothesis that short-term high- dose perioperative atorvastatin treatment reduces the incidence of postoperative AKI in which 270 subjects have already been studied (PI: Billings). In Aim 1 we will test the hypothesis that mitochondrial dysfunction predicts systemic and renal markers of oxidative stress, and we will determine whether markers of mitochondrial function are lower in subjects who developed AKI compared to in subjects who did not. To accomplish Aim 2, we will perform a prospective, randomized, double-blind, placebo-controlled, dose- ranging, clinical study in which we will randomize 90 subjects undergoing cardiac surgery to placebo, 1200 mg, or 2400 mg of ubiquinone-10 five days prior to surgery and daily during hospitalization and test the effect of ubiquinone-10 dose on mitochondrial function and oxidative stress. These studies will provide new tools to examine the contribution of mitochondrial dysfunction to oxidant injury during surgery and AKI and may lead to new treatment strategies for patients undergoing surgery that will be tested in a future trial. Studies will be performed in Vanderbilt University Medical Center operating rooms, intensive care units, and clinics, and in Division of Clinical Pharmacology laboratories. As Associate Dean for Clinical and Translational Scientist Development from 2006-2010, the candidate's mentor built the institutional infrastructure to promote the success of junior physician-scientists and has received numerous awards for successfully mentoring physicians to scientific independence. Her laboratory conducts hypothesis-testing studies in humans and rodents that decipher mechanisms of cardiovascular and renal diseases. The Department of Anesthesiology provides unusual support including 80% protected non-clinical time and a research nurse dedicated exclusively to his research. Strong institutional investment in the candidate optimizes his likelihood of progressing to independence and impacting on adverse effects of surgery.

描述（由申请人提供）：该候选人是一名麻醉学助理教授，正在进行转化研究，测试心脏手术后急性肾损伤 (AKI) 的机制。他的近期职业目标是 1) 测试线粒体功能障碍导致氧化和损伤的假设。心脏手术后的 AKI（参见具体目标）和 2) 获得成为一名独立研究者所需的技能和经验，进行临床试验，测试手术引起的 AKI 的治疗和机制。 1) 提高他提出和严格测试假设的能力，这些假设根据病理生理过程的标记来破译围手术期器官功能障碍的机制；2) 建立、领导和维持对多学科团队的资助，该团队可以测试和开发新的策略，以减少候选人、他的导师和他的指导委员会制定了一个全面的职业发展计划来实现这些目标，该计划的关键要素是急性氧化损伤、线粒体病理生理学的结构化培训。功能障碍和 AKI，与假设检验临床试验设计和性能相关的技术培训，来自不同医师科学家的结构化指导，重点关注科学敏锐度的发展，以及计划的手稿写作、演示文稿构建和资助准备。他已发表了两篇论文。关于 AKI 实验模型的论文以及三篇关于人类 AKI 手术和治疗的炎症/促氧化反应的论文。在资助期间，候选人将测试以下假设：1) 线粒体功能障碍与氧化应激相关。心脏手术并预测心脏手术后 AKI（目标 1）和 2）使用线粒体靶向抗氧化剂泛醌-10 进行治疗可减少接受心脏手术的患者的线粒体功能障碍和氧化应激（目标 2）。术中血浆和尿液氧化损伤标记物（F2-异前列烷和异呋喃）的浓度可预测术后 AKI 的发生。观察到的异呋喃表达可能是通过线粒体功能障碍来解释的，在发生 AKI 的心脏手术患者中，白细胞线粒体 DNA (mtDNA) coy 数显着较低，术中动脉乳酸：丙酮酸比率与术后异呋喃和泛醌浓度相关。 -10 降低慢性肾病患者的异呋喃浓度 为了实现目标 1，考生将测量并比较术前、术中和术后的血浆和尿液浓度。 F2-异前列腺素和异呋喃，线粒体功能标记物（线粒体氧化还原电位、过氧化物酶体增殖物激活受体 ¿共激活剂1-¿完成他汀类 AKI 心脏手术随机临床的 150 名受试者中的 (PGC-1¿) RNA 表达和分离白细胞的 mtDNA 拷贝数以及动脉乳酸：丙酮酸比率）以及临床 AKI（使用 AKI 诊断的 AKIN 分期共识标准定义）试验，一项测试假设围手术期短期大剂量阿托伐他汀治疗可降低术后 AKI 发生率的试验，已对 270 名受试者进行了研究（PI：Billings）在目标 1 中，我们将检验线粒体功能障碍预测氧化应激的全身和肾脏标志物的假设，并且我们将确定发生 AKI 的受试者的线粒体功能标志物是否低于未发生 AKI 的受试者。为了实现目标 2，我们将进行一项前瞻性、随机、双盲、安慰剂对照、剂量范围临床研究，其中我们将 90 名接受心脏手术的受试者随机分配到安慰剂、1200 毫克或手术前五天和住院期间每天服用 2400 毫克泛醌 10，并测试泛醌 10 剂量对线粒体功能和氧化应激的影响。这些研究将为检查线粒体功能障碍对手术期间氧化损伤的影响提供新的工具。 AKI 可能会为接受手术的患者带来新的治疗策略，这些策略将在未来的试验中进行测试，研究将在范德比尔特大学医学中心的手术室、重症监护室、诊所和科室进行。 2006 年至 2010 年，作为负责临床和转化科学家发展的副院长，候选人的导师建立了促进初级医师科学家成功的机构基础设施，并因成功指导医师实现科学独立而获得了众多奖项。在人类和啮齿类动物中进行假设检验研究，以破译心血管和肾脏疾病的机制。麻醉科提供了不同寻常的支持，包括 80% 的非临床时间保护和研究护士专门致力于他的研究。对候选人的强有力的机构投资可以优化他取得独立性并减少手术不良反应的可能性。