New mechanistic therapies for myoglobinuric acute kidney injury

肌红蛋白尿性急性肾损伤的新机制疗法

• 批准号: 9037502
• 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 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9037502
• 关键词: Acute; Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; Affect; Alternative Splicing; Apoptotic; Cell Death; Cells; Chemicals; Complex; DNA; DNA Fragmentation; Deoxyribonuclease I; Development; Disease; Dominant-Negative Mutation; Enzymes; Epithelial; Epithelial Cells; Fluorescent Probes; Funding; Future; General Population; Genes; Glycerol; Goals; Grant Review; Health; Healthcare; Hemin; Hemodialysis; Hemolysis; Hour; Human; In Vitro; Injury; Kidney; Kidney Transplantation; Lead; Life; Mediating; Medical; Methods; Mus; Muscular Atrophy; Myoglobin; Oxidative Stress; Pharmaceutical Preparations; Population; Protein Isoforms; RNA Splicing; Reactive Oxygen Species; Regulation; Research; Rhabdomyolysis; Skeletal Muscle; Testing; Therapeutic; Time; Toxic Environmental Substances; Toxin; Trauma; Tubular formation; Veterans; arm; base; cell injury; cytotoxic; disability; endonuclease; endonuclease G; high throughput screening; high throughput technology; improved; in vitro Model; in vitro testing; in vivo; in vivo Model; inhibitor/antagonist; kidney cell; mRNA Precursor; novel strategies; novel therapeutics; operation; pathogen; prevent; public health relevance; screening; small hairpin RNA; small molecule libraries; tool; translational approach; weapons

DESCRIPTION (provided by applicant): Our 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 that the importance of apoptotic endonuclease G (EndoG) in mediating myoglobinuric AKI is much more complex, not limited to DNA fragmentation only, and in some cases, completely opposite to what was initially accepted. The present proposal is based on our recent unexpected observations that myoglobinuric AKI is mediated by apoptotic deoxyribonuclease I (DNase I) regulated by EndoG. Prior to this study, no regulation of an endonuclease by another endonuclease has been described, and EndoG was considered one of the DNA-fragmenting apoptotic endonucleases. Contrary to this, we found that when EndoG becomes activated by later or stronger injury, it inactivates DNase I and thus protects against the injury. Therefore in the kidney, EndoG acts as cytoprotective enzyme instead of being cytotoxic. We hypothesize that myoglobinuric AKI can be prevented by inducing of EndoG-mediated inactivation of DNase I or otherwise inhibiting expression or activity of DNase I before and/or after injury. Our specific objectives are as follows. In Aim 1, we will evaluate native DNase I- and alternatively-spliced DNase I-based therapeutic approaches to ameliorate myoglobinuric tubular cell injury and AKI. In Aim 2, we plan to determine how EndoG-mediated inactivation of DNase I can be used to blunt myoglobunuric AKI. Aim 3 will be using our new high throughput technology to screen chemical library for new DNase I inhibitors applicable for the treatment of myoglobinuric AKI. 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.

描述（由申请人提供）： 我们的武装部队通常会暴露于危险武器，病原体，环境毒素以及后来的医疗对策，具有长期健康影响。肾脏受到体内排出的许多代谢的毒素的影响，包括横纹肌溶解产物（骨骼肌降解），溶血，药物和外源毒素。这些化合物中有许多通过产生活性氧（ROS）引起急性肾脏损伤（AKI），从而激活凋亡性核酸内切核酸内切叶核。由此产生的急性肾衰竭（AKF）是一种威胁生命的疾病，需要血液透析或肾脏移植。 该提议是延续的 先前的研究由VA功绩审查赠款资助。上一个项目的具体目标已经完成，新目标是这些目标的逻辑扩展。先前研究的结果表明，凋亡性核酸内切酶G（内核）在介导肌球蛋白AKI中的重要性要复杂得多，不仅限于DNA片段化，在某些情况下，与最初接受的情况完全相反。本提案是基于我们最近的意外观察结果，即肌全螺旋尿AKI是由凋亡的脱氧核糖核酸酶I（DNASE I）介导的，该核酸酶I（DNase I）受Endog调节。在这项研究之前，尚未描述另一核酸内切酶对核酸内切酶的调节，并且内og被认为是DNA碎片凋亡的凋亡核酶之一。与此相反，我们发现，当内og被以后或更严重的损伤激活时，它会使DNase I失活，从而防止损伤。因此，在肾脏中，内og充当细胞保护酶，而不是细胞毒性。 我们假设可以通过诱导内og介导的DNase I失活或以其他方式抑制DNase I之前和/或损伤后抑制DNase I的表达或活性来预防肌红素尿AKI。我们的具体目标如下。在AIM 1中，我们将评估天然DNase I和替代性DNase I的基于I的DNase I的治疗方法，以改善肌红细胞性管状细胞损伤和AKI。在AIM 2中，我们计划确定如何使用内og介导的DNase I灭活，以钝化肌球蛋白AKI。 AIM 3将使用我们的新高吞吐量技术来筛选化学库的新DNase I抑制剂，适用于治疗肌红螺旋尿AKI。 对退伍军人卫生保健的潜在影响。这些研究的成功完成可能会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，因为即使在肾脏受伤后进行给药，它们即使行动也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允许挽救人类的生命，改善退伍军人的健康，并减少退伍军人人口中的残疾人数。