DNase-Targeted Mitigation of Acute Kidney Injury Due to Rhabdomyolysis

美国武装部队经常接触危险武器、病原体， 环境毒素，以及后来对健康产生长期影响的医疗对策。的 肾脏受到体内代谢的许多毒素的影响，这些毒素包括 横纹肌溶解（骨骼肌降解）、溶血、药物和外源性毒素。许多 这些化合物通过产生活性氧引起急性肾损伤（阿基 (ROS)，其激活凋亡核酸内切酶。急性肾衰竭（AKF）是一种 危及生命的情况，需要血液透析或肾移植。这项建议是一项 继续以前的研究由VA Merit Review补助金资助。具体目标是 以前的项目已经完成，新的目标是这些项目的逻辑延伸 目标。先前研究的结果显示了两种DNA降解酶的重要性， 细胞质脱氧核糖核酸酶I（DNase I）和线粒体核酸内切酶G（EndoG）， 介导由横纹肌溶解诱导的肌红蛋白尿性阿基。我们的数据显示， 酶是以复杂的网络连接在一起的。对核酸内切酶的作用机制进行了梳理 调控，并为将来开发抗核酸内切酶药物，我们已经确定了几种 无毒的核酸内切酶抑制剂，具有很好的药用潜力。我们假设 在肌红蛋白尿阿基期间，（a）由DNA酶I引导的核酸内切酶充当网络，其中 单个酶可以通过DNA断裂相互诱导;（B）EndoG可以通过DNA断裂相互诱导。 通过其RNA酶活性通过选择性剪接（AS）的DNA酶I;和（c）抗核酸内切酶 阿基的治疗或预防应针对单个核酸内切酶和整个 网络我们的具体目标如下。在目标1中，我们将描述DNA酶I介导的 肌红蛋白尿阿基期间核酸内切酶的调节机制。在目标2中，我们计划 定义肌红蛋白尿阿基期间EndoG介导的核酸内切酶调节机制。 目的3将评估用于肾组织保护的核酸内切酶的治疗调节， 评估在其他阿基模型中观察到的调节机制的一般性。 对退伍军人医疗保健的潜在影响。成功完成这些研究可以 可能导致新的治疗工具的开发，以预防或改善 肌红蛋白尿阿基。其中一些将具有很强的翻译价值，因为它们即使在 肾损伤后给药，而其他药物可能成为未来的治疗选择。 当应用于人类时，这项研究的结果可能会拯救人类的生命，改善人类的健康状况。 退伍军人的健康，减少退伍军人中的残疾人数。

The United States Armed Forces are routinely exposed to hazardous weapons, pathogens, environmental toxins and, later, medical countermeasures with long-term health effects. The kidney is affected by many toxins metabolized in the body that it excretes, including products of rhabdomyolysis (skeletal muscle degradation), hemolysis, drugs, and exogenous toxins. Many of these compounds cause acute kidney injury (AKI) by producing reactive oxygen species (ROS), which activate apoptotic endonucleases. The resulting acute kidney failure (AKF) is a life-threatening condition that requires hemodialysis or kidney transplantation. This proposal is a continuation of the previous research funded by a VA Merit Review grant. The specific aims in the previous project have been accomplished and the new goals are logical extensions of these aims. The results from the previous study show the importance of two DNA-degrading enzymes, cytoplasmic deoxyribonuclease I (DNase I) and mitochondrial endonuclease G (EndoG) in mediating myoglobinuric AKI induced by rhabdomyolysis. Our data indicate that the two enzymes are linked in a sophisticated network. To sort out the mechanisms of endonuclease regulation, and to develop an anti-endonuclease drugs for the future, we have identified several non-toxic endonuclease inhibitors with promising pharmaceutical potentials. We hypothesize that during myoglobinuric AKI, (a) endonucleases led by DNase I act as a network in which individual enzymes can induce each other through DNA breaks; (b) EndoG can inactivate DNase I by alternative splicing (AS) through its RNase activity; and (c) anti-endonuclease therapy or prevention of AKI should be aimed at both individual endonucleases and the entire network. Our specific objectives are as follows. In Aim 1, we will delineate DNase I-mediated mechanisms of regulation of endonucleases during myoglobinuric AKI. In Aim 2, we plan to define EndoG-mediated mechanisms of regulation of endonucleases during myoglobinuric AKI. Aim 3 will evaluate therapeutic modulation of endonucleases for kidney tissue protection, and assess the generality of the observed regulatory mechanisms in other AKI models. Potential Impact on Veterans Health Care. Successful completion of these studies can potentially lead to the development of new therapeutic tools to prevent or ameliorate myoglobinuric AKI. Some of them will have strong translational value because they act even if administered after kidney injury, while others can become therapeutic options of the future. When applied to humans, the results of this study may allow saving human lives, improving the health of veterans, and decreasing the number of disabilities in the veteran population.