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，以及后来对健康有长期影响的医学对策。这个 肾脏受到体内代谢的许多毒素的影响，这些毒素是它排泄出来的，包括 横纹肌溶解(骨骼肌降解)、溶血、药物和外源性毒素。许多 这些化合物中的一种通过产生活性氧物种而导致急性肾损伤(AKI) (ROS)，激活凋亡的核酸内切酶。由此导致的急性肾功能衰竭(AKF)是一种 需要进行血液透析或肾移植的危及生命的情况。这项建议是一项 由退伍军人事务部功绩审查基金资助的先前研究的继续。其中的具体目标 以前的项目已经完成，新的目标是这些目标的合理扩展 目标。先前研究的结果表明了两种DNA降解酶的重要性， 胞质脱氧核糖核酸酶I(DNase I)和线粒体内切酶G(Endog) 介导横纹肌溶解诱导的肌红蛋白尿AKI。我们的数据显示，这两个 酶在一个复杂的网络中相连。理清核酸内切酶的作用机制 为了规范和开发一种未来的抗核酸内切酶药物，我们已经确定了几种 具有良好药用潜力的无毒核酸内切酶抑制剂。我们假设 在肌红蛋白尿AKI过程中，(A)由DNase I领导的核酸内切酶作为一个网络，在其中 单独的酶可以通过DNA断裂相互诱导；(B)endog可以失活 DNA酶I通过其核糖核酸酶活性进行选择性剪接(AS)；以及(C)抗核酸内切酶 AKI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DNase I介导的 肌红蛋白尿AKI过程中核酸内切酶的调控机制。在目标2中，我们计划 明确Endog介导的肌红蛋白尿AKI过程中核酸内切酶调节机制。 AIM 3将评估核酸内切酶对肾脏组织保护的治疗调节作用，以及 评估在其他AKI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 潜在地导致开发新的治疗工具来预防或改善 肌红蛋白尿酸。其中一些将具有很强的翻译价值，因为它们即使在 在肾脏损伤后使用，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 保障退伍军人的健康，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.