Mitochondrial dysfunction, oxidative stress, and surgical acute kidney injury

描述(由申请人提供)：应聘者是麻醉学助理教授，从事翻译研究，测试心脏手术后急性肾损伤(AKI)的机制。他的直接职业目标是：1)测试线粒体功能障碍会导致心脏手术后氧化和急性心肌梗死的假说(见具体目标)；2)获得所需的技能和经验，成为一名独立的调查员，进行临床试验，测试手术诱发急性心肌梗死的治疗方法和机制。他的长期职业目标是：1)提高他开发和严格测试假说的能力，这些假说根据病理生理过程的标志破译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。这位候选人、他的导师和他的指导委员会已经制定了一项全面的职业发展计划，以实现这些目标。该计划的关键要素是急性氧化损伤、线粒体功能障碍和AKI的病理生理学方面的结构化培训，与假设检验临床试验设计和性能相关的技术培训，来自不同医生和科学家的结构化指导，重点是科学敏锐性的发展，以及预定的手稿写作、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，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。在授予期间，候选人将检验以下假设：1)线粒体功能障碍与心脏手术期间的氧化应激有关，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的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)。这位候选人最近表明，术中血浆和尿氧化性损伤标志物(F2-异前列腺素和异呋喃)的浓度可以预测术后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/丙酮酸比率与术后异呋喃的尿液浓度相关，而泛醌-10降低了慢性肾脏疾病患者的异呋喃浓度。为了实现目标1，候选人将在完成他汀类AKI心脏手术随机临床试验的150名受试者中测量和比较术前、术中和术后血浆和尿中F2-异前列腺素和异呋喃浓度、线粒体功能标志物(线粒体氧化还原电位、过氧化物酶体增殖物激活受体1-β(PGC-1)RNA表达、分离白细胞的mtDNA拷贝数和动脉乳酸：丙酮酸比率)和临床AKI(使用AKI诊断的AKI分期共识标准定义)。一项试验验证了围手术期短期大剂量阿托伐他汀治疗降低术后AKI发生率的假设，该试验已经对270名受试者进行了研究(PI：Billings)。在目标1中，我们将测试线粒体功能障碍预测全身和肾脏氧化应激标志物的假设，我们将确定发生AKI的受试者是否比没有发生AKI的受试者线粒体功能标记物更低。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、剂量范围的临床研究，在这项研究中，我们将随机选择90名心脏手术受试者，在手术前五天和住院期间每天服用安慰剂、1200 mg或2400 mg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。这些研究将提供新的工具，以检查线粒体功能障碍对手术和AKI期间氧化损伤的贡献，并可能为接受手术的患者带来新的治疗策略，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手术室、重症监护病房和诊所以及临床药理学实验室进行。在2006-2010年间担任临床和转化科学家发展副院长期间，候选人的导师建立了促进初级医生-科学家成功的机构基础设施，并因成功地指导医生实现科学独立而获得了许多奖项。她的实验室在人类和啮齿动物身上进行假设检验研究，破译心血管和肾脏疾病的机制。麻醉学系提供不同寻常的支持，包括80%受保护的非临床时间和一名专门致力于他的研究的研究护士。对候选人的强有力的机构投资优化了他走向独立的可能性，并对手术的不利影响产生了影响。

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.