Urinary Biomarkers of Renal Mitochondrial Dysfunction

肾线粒体功能障碍的尿液生物标志物

• 批准号: 9055870
• 负责人: Rick G Schnellmann
• 金额: $ 19.42万
• 依托单位: MITOHEALTH, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9055870
• 关键词: Urinary; Biomarkers; Renal; Mitochondrial; Dysfunction

DESCRIPTION (provided by applicant): The long-term goal of this project is to identify and validate biomarkers of mitochondrial dysfunction due to environmental stressors. Diverse acute insults from surgery, trauma, ischemia/reperfusion (I/R) and drug and environmental chemical toxicity lead to mitochondrial dysfunction and result in cell injury and death in many organs/tissues (e.g. heart, lung, brain, liver and kidney). Furthermore, mitochondrial dysfunction can contribute to cell injury through increased production of reactive oxygen and nitrogen species. Mitochondrial dysfunction is also a component of many chronic diseases such as metabolic syndrome, diabetes, neurodegenerative diseases, and aging. Consequently, there is a great need for non-invasive biomarkers of mitochondrial dysfunction. We hypothesize that urinary mitochondrial DNA (mtDNA) and urinary protein levels of mitochondrial ATP synthase (ATPS) subunits are sensitive and specific markers of mitochondrial dysfunction in acute kidney injury (AKI). Our preliminary studies support this hypothesis by demonstrating increased urinary mtDNA and ATPS in mice subjected to I/R induced AKI when renal mitochondrial dysfunction was present. These preliminary studies provide strong evidence in support of our hypothesis. The following Specific Aims will be examined: 1) Using a mouse model with different degrees of I/R induced AKI, elucidate urinary changes in mtDNA, mitochondrial ATPS subunits and other mitochondrial proteins; integrate these changes with renal mitochondrial dysfunction over time; and compare and contrast the changes in these endpoints with general urinary AKI biomarkers. These studies will result in new urinary markers of mitochondrial dysfunction in animals. Comparison of mitochondrial DNA, protein and function over a range of times and grades of injury will permit better understanding of the timing and mechanisms of injury and recovery. Finally, these biomarkers can be tested in humans and translated into laboratory and clinical practice.

描述（由申请人提供）：该项目的长期目标是识别和验证由于环境压力导致的线粒体功能障碍的生物标志物。来自手术、创伤、缺血/再灌注（I/R）以及药物和环境化学毒性的各种急性损伤导致线粒体功能障碍，并导致许多器官/组织（例如心脏、肺、脑、肝和肾）中的细胞损伤和死亡。此外，线粒体功能障碍可通过增加活性氧和氮物质的产生而导致细胞损伤。线粒体功能障碍也是许多慢性疾病如代谢综合征、糖尿病、神经退行性疾病和衰老的组成部分。因此，非常需要线粒体功能障碍的非侵入性生物标志物。我们假设，尿线粒体DNA（mtDNA）和尿蛋白水平的线粒体ATP合酶（ATPS）亚基是敏感和特异性的标志物线粒体功能障碍在急性肾损伤（阿基）。我们的初步研究支持这一假设，证明增加尿mtDNA和ATPS的小鼠受到I/R诱导的阿基时，肾线粒体功能障碍。这些初步研究为支持我们的假设提供了强有力的证据。将检查以下特定目的：1）使用具有不同程度I/R诱导的阿基的小鼠模型，阐明mtDNA、线粒体ATPS亚基和其他线粒体蛋白的尿变化;将这些变化与随时间推移的肾线粒体功能障碍整合;并将这些终点的变化与一般尿阿基生物标志物进行比较和对比。这些研究将产生新的动物线粒体功能障碍的尿液标志物。比较线粒体DNA，蛋白质和功能在一系列时间和损伤等级将允许更好地理解损伤和恢复的时间和机制。最后，这些生物标志物可以在人体中进行测试，并转化为实验室和临床实践。