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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的在该奖项颁发的过去十年中，我们在了解不利因素方面取得了实质性进展慢性肾脏病（CKD）对老年人健康的影响。肾功能逐渐衰退年龄，即使没有任何临床危险因素，肾功能下降也与以下因素密切相关：无数的心血管和非心血管疾病。除了肾小球损伤外，我们还有了解到肾小管功能障碍、纤维化和损伤可预测不良的临床结果。这些结果表明肾小管健康对于了解肾脏的发育和进展至关重要疾病。在影响老年人的肾外疾病（如心力衰竭或痴呆）中，线粒体功能障碍似乎在发病机制中起重要作用。与心脏和大脑一样，肾小管也依赖于依靠线粒体能量代谢来支持器官的基本功能。在这次更新中，我们假设线粒体健康状况下降是老年人肾脏疾病的一个主要原因，其驱动因素是线粒体丰度减少和氧化功能障碍是由线粒体累积突变引起的线粒体DNA（mtDNA）。我们的新初步数据表明循环 mtDNA、肾内线粒体健康和肾功能结果。随着人们对线粒体的治疗兴趣不断兴起，这该提案还可能带来预防和治疗 CKD 的新疗法。我们将利用 mtDNA 的创新通过新开发的下一代测序评估其拷贝数的数量和质量突变负荷的方法。已发表的结果已经将这些措施与整体老龄化联系起来。我们将申请这些技术跨越三个转化目标：前两个目标将在大型、良好的特征队列和第三个目标将使用人类肾组织。第一个目标将评估是否线粒体DNA的数量和质量与接受心脏手术的人发生急性肾损伤的风险相关外科手术。第二个目标将评估相同 mtDNA 测量与 CKD 发展的关联并进展为肾衰竭。第三个目标将利用一套经过验证的技术来调查使用来自患有或不患有肾脏疾病的老年人的存档肾组织进行原位线粒体健康：我们将比较线粒体生物合成、线粒体数量、氧化磷酸化能力的测量值，和超微结构外观，然后评估它们与组织病理学和临床状态的关联。这些目标将把线粒体的新兴肾脏生物学转化为老年人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，作为潜在的治疗靶点肾脏疾病； 2）开发评估肾组织线粒体的创新方法；和 3) 为未来针对线粒体的疗法的临床试验选择患者提供信息。