DNase-Targeted Mitigation of Acute Kidney Injury Due to Rhabdomyolysis

DNase 靶向缓解横纹肌溶解引起的急性肾损伤

• 批准号: 10292439
• 负责人: Alexei G Basnakian
• 金额: --
• 依托单位: CENTRAL ARKANSAS VETERANS HLTHCARE SYS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292439
• 关键词: Acute; Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; Affect; Alternative Splicing; Apoptotic; Cell Death; Cell Nucleus; Chemicals; Cisplatin; Cultured Cells; DNA; DNA Fragmentation; DNA biosynthesis; Data; Deoxyribonuclease I; Deoxyribonucleases; Development; Disasters; Disease; Enzymes; Epithelial; Epithelial Cells; Event; Exposure to; Extravasation; Fluorescence; Funding; Future; Glycerol; Goals; Grant Review; Health; Healthcare; Hemin; Hemodialysis; Hemolysis; Human; In Vitro; Individual; Injury; Injury to Kidney; Intervention; Ischemia; Kidney; Kidney Transplantation; Knockout Mice; Laboratories; Lead; Life; Link; Measurement; Mediating; Methods; Military Personnel; Mitochondria; Modeling; Mus; Muscular Atrophy; Mutate; Myoglobin; Nuclear; Organ; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Prevention; Prevention strategy; Prognosis; RNA; RNA chemical synthesis; Reactive Oxygen Species; Regulation; Reperfusion Therapy; Reporting; Research; Rhabdomyolysis; Ribonucleases; Role; Savings; Skeletal Muscle; Small Interfering RNA; Testing; Therapeutic; Tissues; Toxic Environmental Substances; Toxin; Trauma; Tubular formation; United States; Veterans; base; cell injury; clinically relevant; disability; endonuclease; endonuclease G; expression vector; gene cloning; improved; in vitro Model; in vivo; inhibitor; kidney cell; medical countermeasure; military veteran; novel; novel strategies; novel therapeutics; operation; pathogen; prevent; tool; weapons

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.

美国武装部队经常暴露于危险武器、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。这 肾脏受到体内代谢并排泄的许多毒素的影响，包括 横纹肌溶解症（骨骼肌退化）、溶血、药物和外源性毒素。许多 这些化合物通过产生活性氧而引起急性肾损伤 (AKI) (ROS)，激活细胞凋亡核酸内切酶。由此产生的急性肾衰竭（AKF）是 危及生命的疾病，需要血液透析或肾移植。该提案是一个 继续先前由 VA 优异评审拨款资助的研究。具体目标在 之前的项目已经完成，新的目标是这些目标的逻辑延伸 目标。之前的研究结果显示了两种 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) 介导横纹肌溶解引起的肌红蛋白尿 AKI。我们的数据表明，两者 酶连接在一个复杂的网络中。理清核酸内切酶的机制 监管，并为未来开发抗核酸内切酶药物，我们已经确定了几种 无毒核酸内切酶抑制剂，具有良好的药物潜力。我们假设 在肌红蛋白尿性 AKI 期间，(a) 由 DNase I 领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 可以失活 DNase I 通过其 RNase 活性进行选择性剪接 (AS)； (c) 抗核酸内切酶 AKI 的治疗或预防应针对个体核酸内切酶和整个核酸内切酶。 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 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 AKI 期间 EndoG 介导的核酸内切酶调节机制。 目标 3 将评估核酸内切酶对肾组织保护的治疗调节作用，以及 评估其他 AKI 模型中观察到的调节机制的普遍性。 对退伍军人医疗保健的潜在影响。成功完成这些研究可以 可能导致开发新的治疗工具来预防或改善 肌红蛋白尿 AKI。其中一些具有很强的转化价值，因为即使 肾损伤后给药，而其他药物则可以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 退伍军人的健康，并减少退伍军人中的残疾人数。