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.

美国武装部队通常会暴露于危险武器，病原体， 环境毒素，后来是具有长期健康影响的医学对策。这 肾脏受到其排泄的体内代谢的许多毒素的影响，包括 横纹肌溶解（骨骼肌降解），溶血，药物和外源毒素。许多 在这些化合物中，通过产生活性氧引起急性肾脏损伤（AKI） （ROS），激活凋亡的核酸内切酶。由此产生的急性肾衰竭（AKF）是 威胁生命的状况，需要血液透析或肾脏移植。该建议是 由VA功绩审查赠款资助的先前研究的延续。具体目的 上一个项目已经完成，新目标是这些项目的逻辑扩展 目标。先前研究的结果表明，两种DNA降解酶的重要性， 细胞质脱氧核糖核酸酶I（DNase I）和线粒体内核酸酶G（内核）G（内核） 介导由横纹肌溶解诱导的肌红尿AKI。我们的数据表明这两个 酶在复杂的网络中链接。清理核酸内切酶的机制 监管并为未来开发抗核酸酶药物，我们已经确定了几个 具有有希望的药物潜力的无毒内切核酸内切酶抑制剂。我们假设 在Myoglobiner aki中 单个酶可以通过DNA断裂相互诱导。 （b）内传会灭活 DNase I通过其RNase活性通过替代剪接（AS）； （c）抗核酸酶 治疗或预防AKI应针对单个内切核和整个核酸 网络。我们的具体目标如下。在AIM 1中，我们将描述DNase I介导的DNase 在肌全尿AKI期间的核珠调节调节机制。在AIM 2中，我们计划 定义肌全核AKI期间内切核酸酶调节的内og介导的机制。 AIM 3将评估肾脏组织保护核酸内切酶的治疗调节，并 评估其他AKI模型中观察到的调节机制的通用性。 对退伍军人卫生保健的潜在影响。这些研究的成功完成可以 有可能导致开发新的治疗工具，以预防或改善 肌球蛋白Aki。他们中的一些人将具有强大的翻译价值，因为它们的行为即使 在肾脏受伤后进行管理，而其他人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可以挽救人类的生命，改善 退伍军人的健康，减少退伍军人人口的残疾人数。