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源引起的线粒体功能障碍的生物标志物。手术，创伤，缺血/再灌注（I/R）以及药物和环境化学毒性导致线粒体功能障碍，导致许多器官/组织（例如心脏，肺，脑，肝脏和肾脏）导致细胞损伤和死亡导致细胞损伤和死亡。此外，线粒体功能障碍可以通过增加活性氧和氮种的产生来导致细胞损伤。线粒体功能障碍也是许多慢性疾病的组成部分，例如代谢综合征，糖尿病，神经退行性疾病和衰老。因此，非常需要线粒体功能障碍的非侵入性生物标志物。我们假设线粒体ATP合酶（ATP）亚基是急性肾损伤（AKI）中线粒体功能障碍的敏感和特定标记的线粒体ATP合酶（ATP）亚基的尿线粒体DNA（mtDNA）和尿蛋白水平。我们的初步研究通过证明肾脏线粒体功能障碍存在I/R引起的AKI的小鼠中的尿液mtDNA和ATP来支持这一假设。这些初步研究为支持我们的假设提供了有力的证据。将检查以下特定目的：1）使用具有不同程度的I/R诱导的AKI的小鼠模型，阐明mtDNA，线粒体ATPS亚基和其他线粒体蛋白的尿发生变化；随着时间的流逝，这些变化与肾脏线粒体功能障碍相结合；并将这些终点的变化与一般的尿尿AKI生物标志物进行比较和对比。这些研究将导致动物线粒体功能障碍的新尿标志物。线粒体DNA，蛋白质和功能在多个时间和损伤中的比较将可以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类中进行测试，并将其转化为实验室和临床实践。