Role of Mitochondrial Health in Acute and Chronic Kidney Disease in Older Adults

线粒体健康在老年人急慢性肾脏病中的作用

• 批准号: 9752435
• 负责人: Samir M Parikh
• 金额: $ 71.14万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752435
• 关键词: Activities of Daily Living; Acute; Acute Renal Failure with Renal Papillary Necrosis; Adult; Affect; Age; Aging; Apoptosis; Appearance; Archives; Atherosclerosis Risk in Communities; Award; Bioenergetics; Biogenesis; Biology; Blood; Body Composition; Boston; Brain; Cardiac Surgery procedures; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Chronic Kidney Failure; Clinical; Clinical Trials; Cohort Studies; DNA copy number; DNA sequencing; Data; Defect; Dementia; Development; Diagnostic; Disease Progression; Elderly; Energy Metabolism; Fibrosis; Functional disorder; Future; Generations; Genes; Genome; Glomerular Filtration Rate; Health; Heart; Heart failure; Histopathology; Hospitals; Human; Impairment; In Situ; Individual; Injury; Injury to Kidney; Intervention; Investigation; Kidney; Kidney Diseases; Kidney Failure; Lead; Life; Link; Measurement; Measures; Methods; Mitochondria; Mitochondrial DNA; Morbidity - disease rate; Morphology; Mutation; Nephrectomy; Neuraxis; Onset of illness; Organ; Outcome; Oxidative Phosphorylation; PPAR gamma; Participant; Pathogenesis; Pathogenicity; Patient Selection; Persons; Postoperative Period; Predisposition; Prevalence; Process; Public Health; Publishing; Reactive Oxygen Species; Recovery; Renal function; Renal tubule structure; Resistance; Risk; Risk Factors; Role; Skeletal Muscle; Somatic Mutation; Specimen; Stains; Structure; Techniques; Technology; Therapeutic; Therapy Clinical Trials; Tissues; Translating; Tubular formation; Woman; Work; age effect; base; candidate marker; clinical risk; cohort; follow-up; frailty; genetic epidemiology; high risk; human study; innovation; interest; kidney biopsy; kidney fibrosis; mitochondrial DNA mutation; mitochondrial dysfunction; mortality; neurosensory; next generation sequencing; novel therapeutics; peripheral blood; preservation; prevent; response biomarker; targeted therapy trials; targeted treatment; therapeutic target

ABSTRACT Over the past decade of this award, we have made substantial progress toward understanding the adverse impact of chronic kidney disease (CKD) on the health of older adults. Kidney function declines steadily with age, even in the absence of any clinical risk factors, and reduced kidney function is strongly associated with myriad cardiovascular and non-cardiovascular morbidities. In addition to glomerular impairments, we have learned that kidney tubule dysfunction, fibrosis, and injury predict adverse clinical outcomes. These results suggest that kidney tubular health is pivotal for understanding the development and progression of kidney disease. In extrarenal conditions affecting older adults such as heart failure or dementia, mitochondrial dysfunction appears to have a major role in pathogenesis. Like the heart and brain, the kidney tubules rely upon mitochondrial energy metabolism to support fundamental functions of the organ. In this renewal, we hypothesize that reduced mitochondrial health is a major cause of kidney disease in older adults, driven by reduced mitochondrial abundance and oxidative dysfunction that results from accumulated mutations in the mitochondrial DNA (mtDNA). Our new preliminary data implicate unexpectedly striking relationships between circulating mtDNA, intrarenal mitochondrial health, and functional renal outcomes. With emerging therapeutic interest in mitochondria, this proposal could also lead to novel therapies to prevent and treat CKD. We will leverage innovations in mtDNA assessment to measure its quantity by copy number and its quality by newly developed next-gen sequencing methods for mutation burden. Published results already link these measures to overall aging. We will apply these techniques across three translational Aims: the first two Aims will be conducted in large, well- characterized cohorts and the third Aim will use human kidney tissue. The first Aim will evaluate whether mtDNA quantity and quality are associated with risk for acute kidney injury in persons undergoing cardiac surgery. The second Aim will evaluate associations of the same mtDNA measures with development of CKD and with progression to kidney failure. The third Aim will utilize a suite of validated techniques to investigate mitochondrial health in situ using archived kidney tissue from older adults with and without kidney disease: we will compare measures of mitochondrial biogenesis, mitochondrial quantity, oxidative phosphorylation capacity, and ultrastructural appearance, and then evaluate their associations with histopathology and clinical status. These Aims will translate the emerging renal biology of mitochondria into human kidney disease in older adults. Positive results would: 1) advance mtDNA quantity and quality as potential therapeutic targets for kidney diseases; 2) develop innovative methods for the assessment of mitochondria in kidney tissue; and 3) inform selection of patients for future clinical trials of therapies targeted to the mitochondria.

抽象的 在该奖项的过去十年中，我们在理解不利方面取得了重大进展 慢性肾脏疾病（CKD）对老年人健康的影响。肾功能稳步下降 即使没有任何临床危险因素，年龄，肾功能降低也与 无数心血管和非心血管病毒。除了肾小球障碍，我们还有 了解到肾小管功能障碍，纤维化和损伤预测了不良临床结果。这些结果 建议肾小管健康对于理解肾脏的发展和进展至关重要 疾病。在影响老年人（例如心力衰竭或痴呆）的肾外状况下，线粒体 功能障碍似乎在发病机理中起主要作用。像心脏和大脑一样，肾小管依靠 线粒体能量代谢支持器官的基本功能。在这种续约中，我们 假设降低线粒体健康是老年人肾脏疾病的主要原因，由 线粒体丰度和氧化功能障碍降低，这是由于在 线粒体DNA（mtDNA）。 我们的新初步数据暗示了循环mtDNA，肾内的意外突击关系 线粒体健康和功能性肾脏结局。有了新兴的线粒体治疗兴趣， 提案还可能导致预防和治疗CKD的新型疗法。我们将利用mtdna的创新 评估以通过拷贝数及其质量衡量其数量通过新开发的下一代测序 突变负担的方法。已发表的结果已经将这些措施与整体衰老联系起来。我们将申请 这些技术在三个翻译目标中的这些技术：前两个目标将以大型，良好的方式进行 表征的队列和第三个目标将使用人类肾脏组织。第一个目标将评估是否 mtDNA数量和质量与患有心脏的人急性肾脏损伤有关 外科手术。第二个目的将评估同一mtDNA措施与CKD的发展的关联 并发展为肾衰竭。第三个目标将利用一套经过验证的技术进行调查 线粒体健康原位使用来自有或没有肾脏疾病的老年人的存档肾脏组织：我们 将比较线粒体生物发生，线粒体量，氧化磷酸化能力的度量， 和超微结构外观，然后评估他们与组织病理学和临床状况的关联。 这些目标将使线粒体的新兴肾脏生物学转化为年龄较大的人类肾脏疾病 成年人。积极的结果将：1）提高mtDNA的数量和质量，作为潜在的治疗靶标 肾脏疾病； 2）开发用于评估肾脏组织线粒体的创新方法； 3） 告知选择患者的未来针对线粒体疗法的临床试验。