Mitochondrial Dysfunction in Chronic Kidney Disease

慢性肾脏病的线粒体功能障碍

• 批准号: 9094590
• 负责人: Jorge Luis Gamboa
• 金额: $ 15.22万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-10 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9094590
• 关键词: Acute; Affect; Age; Alteplase; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Atherosclerosis; Award; Biogenesis; Biology; Biopsy; Bradykinin; Bradykinin B2 Receptor; Cardiovascular system; Cells; Chronic; Chronic Kidney Failure; Clinical; Clinical Pharmacology; Clinical Trials; Creatinine; Cross-Over Studies; Data; Development; Development Plans; Doctor of Philosophy; Double-Blind Method; End stage renal failure; Enrollment; Environment; Etiology; Event; Exhibits; Functional disorder; Funding; General Population; Goals; Gold; Health; Hemodialysis; Hour; Human; In Vitro; Individual; Inflammation; Institution; Intervention; Junior Physician; Kallikrein-Kinin System; Kentucky; Kidney Diseases; Kinins; Lead; Magnetic Resonance Spectroscopy; Maintenance; Measures; Mentors; Methods; Mitochondria; Morbidity - disease rate; Muscle; Oxidative Stress; Participant; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Physicians; Physiology; Placebo Control; Placebos; Plasma; Play; Positioning Attribute; Procedures; Process; Production; Race; Ramipril; Randomized; Reactive Oxygen Species; Recovery; Renal Replacement Therapy; Research; Research Infrastructure; Research Personnel; Risk; Rodent; Role; Scientist; Source; Staging; Superoxides; System; Testing; Time; Training; United States; United States National Institutes of Health; Universities; Vasodilation; base; cardiovascular risk factor; career; career development; density; diabetic; icatibant; improved; in vivo; mitochondrial dysfunction; mortality; novel therapeutic intervention; post-doctoral training; prevent; protective effect; sex; skills; success; valsartan

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) affects approximately 26 million people in the United States. End stage renal disease (ESRD), the final stage of CKD, requires renal replacement therapy such as hemodialysis (HD). Patients undergoing HD are at increased risk of developing cardiovascular complications, and this risk is not explained by traditional cardiovascular risk factors. Other factors such as inflammation and oxidative stress may contribute to the pathophysiology of cardiovascular events in patients with ESRD. We have previously shown that bradykinin plays a role in inflammation in patients on HD and increases oxidative stress in vitro. Mitochondria are one of the main sources of oxidative stress; however the role of mitochondrial dysfunction in ESRD is not yet understood. The overarching goal of this study is to determine the role of progressive CKD and the activation of the kalikrein-kinin system during HD on the development of mitochondrial dysfunction; we will measure mitochondrial function using the gold standard method, 31P magnetic resonance spectroscopy. In Specific Aim 1 we will test the hypothesis that mitochondrial function worsen with the progression of kidney disease. We will compare patients undergoing chronic HD, patients with CKD not yet on HD, and control subjects without CKD. Participants will be matched by age, sex, diabetic status, and BMI. In Specific Aim 2 we will test the hypothesis that endogenous bradykinin promotes mitochondrial dysfunction in patients undergoing HD. We will first perform a randomized, placebo-controlled, double-blind, cross-over study measuring the effect of HOE-140 (Icatibant), a bradykinin B2 receptor blocker, on mitochondrial function. We will also evaluate patients undergoing HD that have been treated for 3 months with the ACE inhibitor ramipril versus the ARB valsartan or placebo, as part of an ongoing NIH funded clinical trial (NCT00878969). We anticipate that bradykinin B2 receptor blockade with HOE-140 will improve mitochondrial function during HD; whereas ramipril, which increases endogenous bradykinin, will worsen mitochondrial function. The candidate obtained his Ph.D. in Physiology in the University of Kentucky and completed postdoctoral training in Clinical Pharmacology at Vanderbilt University. The candidate has studied mitochondrial biology and muscle physiology in rodents, and has conducted a clinical trial in patients with CKD. This award will allow the candidate to strengthen his expertise in studying mitochondrial function in humans and to acquire the skills necessary for an independent career as a physician-scientist. Dr. Nancy J. Brown (candidate's mentor) is an NIH-funded investigator with a successful record of mentoring physicians to scientific independence. As Associate Dean for Clinical Translational Scientist Development (2006 to 2010), Dr. Brown developed the infrastructure and environment to promote the success of junior physician-scientists. The institution is committed to the success of the candidate's career development plan and the completion of the research plan.

描述（由申请人提供）：慢性肾脏疾病（CKD）影响美国约2600万人。 CKD的最后阶段末期肾脏疾病（ESRD）需要肾脏替代疗法，例如血液透析（HD）。接受高清的患者患心血管并发症的风险增加，这种风险并未通过传统的心血管危险因素来解释。诸如炎症和氧化应激之类的其他因素可能有助于ESRD患者心血管事件的病理生理学。我们先前已经表明，心动激肽在HD患者的炎症中起作用，并在体外增加氧化应激。线粒体是氧化应激的主要来源之一。但是，线粒体功能障碍在ESRD中的作用尚不清楚。这项研究的总体目的是确定渐进性CKD的作用以及HD期间Kalikrein-Kinin System在线粒体功能障碍发展过程中的激活；我们将使用金标准方法（31p磁共振光谱法）测量线粒体功能。在特定目标1中，我们将检验以下假设：线粒体功能随肾脏疾病的进展而恶化。我们将比较接受慢性高清的患者，尚未在HD上的CKD患者以及没有CKD的对照受试者。参与者将与年龄，性别，糖尿病状态和BMI相匹配。在特定的目标2中，我们将检验以下假设：内源性心动激肽促进HD患者的线粒体功能障碍。我们将首先进行一项随机，安慰剂对照的双盲，跨界研究，以测量Bradykinin B2受体阻滞剂HOE-140（ICATIBANT）对线粒体功能的影响。我们还将评估正在接受ACE抑制剂Ramipril与ARB Valsartan或安慰剂治疗3个月的HD患者，这是一项正在进行的NIH资助临床试验（NCT00878969）的一部分。我们预计Bradykinin B2受体与HOE-140的阻塞将在HD期间改善线粒体功能。雷米普里（Ramipril）增加了内源性心动激肽，但会使线粒体功能恶化。 候选人获得了他的博士学位。肯塔基大学的生理学博士学位，并在范德比尔特大学完成了临床药理学博士后培训。该候选人研究了啮齿动物的线粒体生物学和肌肉生理，并在CKD患者中进行了临床试验。该奖项将使候选人能够增强他在研究人类线粒体功能方面的专业知识，并获得独立职业作为医生科学家所必需的技能。南希·布朗（Nancy J. Brown）（候选人的导师）是一名由NIH资助的研究员，成功地指导医生以进行科学独立。作为临床转化科学家发展的副院长（2006年至2010年），布朗博士开发了基础设施和环境，以促进初级医师科学家的成功。该机构致力于候选人的职业发展计划和研究计划的完成。