Urinary Biomarkers of Renal Mitochondrial Dysfunction

描述（由申请人提供）：该项目的长期目标是鉴定和验证环境应激因素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引起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（如心、肺、脑、肝和肾）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活性氮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一个组成部分。因此，对线粒体功能障碍的非侵入性生物标志物有很大的需求。我们假设尿线粒体DNA （mtDNA）和线粒体ATP合成酶（ATPS）亚基的尿蛋白水平是急性肾损伤（AKI）中线粒体功能障碍的敏感和特异性标志物。我们的初步研究证实，当肾线粒体功能障碍存在时，I/R诱导AKI小鼠的尿mtDNA和ATPS增加，从而支持了这一假设。这些初步研究为支持我们的假设提供了有力的证据。研究的具体目的如下：1)通过不同程度I/R诱导AKI的小鼠模型，阐明尿中mtDNA、线粒体ATPS亚基和其他线粒体蛋白的变化；随着时间的推移，将这些变化与肾线粒体功能障碍结合起来；并将这些终点的变化与一般尿AKI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尿液标记物。线粒体DNA、蛋白质和功能在一定时间和损伤等级范围内的比较将有助于更好地理解损伤和恢复的时间和机制。最后，这些生物标记物可以在人体中进行测试，并转化为实验室和临床实践。

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.