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: 8354074
• 负责人: Frederic Tremaine Billings
• 金额: $ 18.08万
• 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/8354074
• 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. PUBLIC HEALTH RELEVANCE: Oxidative stress contributes to the kidney injury that complicates recovery in up to 30% of cardiac surgery patients and independently predicts long-term morbidity and death. This study examines mitochondrial dysfunction, oxidative stress, and acute kidney injury in patients undergoing cardiac surgery and tests whether giving a mitochondria-targeted antioxidant reduces mitochondrial dysfunction and oxidative stress in these patients.

描述（由申请人提供）：该候选人是麻醉学助理教授，从事心脏手术后急性肾损伤（AKI）机制的转化研究。他近期的职业目标是：1)验证线粒体功能障碍导致心脏手术后氧化性和AKI的假设（见具体目标）；2)获得所需的技能和经验，成为一名独立的研究者，进行临床试验，测试手术诱发AKI的治疗方法和机制。他的长期职业目标是：1)提高他的能力，发展和严格检验假说，根据病理生理过程的标记来解释围手术期器官功能障碍的机制；2)建立、领导和维持一个多学科团队的资金，该团队可以测试和开发新的策略，以减少手术患者的急性器官功能障碍。候选人、他的导师和他的导师委员会已经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、线粒体功能障碍和AKI病理生理学的结构化培训，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，重点是科学敏锐性的发展，以及预定的手稿撰写、演示文稿构建和拨款准备。他发表了两篇关于AKI实验模型的论文和三篇关于AKI手术和治疗对人类炎症/促氧化反应的论文。在资助奖励期间，候选人将验证以下假设：1)线粒体功能障碍与心脏手术期间的氧化应激相关，并预测心脏手术后的AKI（目标1）；2)线粒体靶向抗氧化剂泛醌- 10治疗可减少心脏手术患者的线粒体功能障碍和氧化应激（目标2）。该候选人最近表明，术中血浆和尿液中氧化损伤标志物（f2 -异前列腺素和异呋喃）的浓度可预测术后AKI的发展。观察到的F2-异前列腺素和异呋喃的表达模式可能与线粒体功能障碍有关。在其他初步研究中，发生AKI的心脏手术患者的白细胞线粒体DNA (mtDNA) coy数显著降低，术中动脉乳酸：丙酮酸比值与术后尿异呋喃浓度相关，泛醌-10降低慢性肾病患者的异呋喃浓度。为了完成目标1，候选人将测量和比较术前、术中和术后血浆和尿液中f2 -异前列腺素和异脲的浓度、线粒体功能的标志物（线粒体氧化还原电位、过氧化物酶体增殖体激活受体辅激活物1- (PGC-1) RNA表达、分离白细胞mtDNA拷贝数和动脉乳酸：丙酮酸比值）。在完成他汀类AKI心脏手术随机临床试验的150名受试者中，临床AKI（使用AKI诊断的AKIN分期共识标准定义），该试验验证了短期高剂量围手术期阿托伐他汀治疗降低术后AKI发生率的假设，其中已有270名受试者进行了研究（PI: Billings）。在Aim 1中，我们将验证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，我们将确定发生AKI的受试者的线粒体功能标志物是否比未发生AKI的受试者低。为了完成目标2，我们将进行一项前瞻性、随机、双盲、安慰剂对照、剂量范围的临床研究，我们将90名接受心脏手术的受试者随机分配给安慰剂、1200毫克或2400毫克的泛素-10，术前5天，住院期间每天服用，并测试泛素-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和AKI期间氧化损伤的贡献提供新的工具，并可能为接受手术的患者提供新的治疗策略，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、重症监护病房、诊所和临床药理学实验室进行。作为2006-2010年临床和转化科学家发展副院长，候选人的导师建立了制度基础设施，以促进初级医师科学家的成功，并因成功指导医生实现科学独立而获得无数奖项。她的实验室在人类和啮齿动物中进行假设测试研究，以破译心血管和肾脏疾病的机制。麻醉科提供不寻常的支持，包括80%的非临床时间和一名专门从事研究的研究护士。对候选人进行强有力的机构投资可以优化其独立发展的可能性，并影响手术的不良影响。