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

基本信息

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
项目类别：
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

项目摘要

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）：我们的武装部队经常接触危险武器、病原体、环境毒素，以及随后对健康产生长期影响的医疗对策。肾脏受到体内代谢并排出的许多毒素的影响，包括横纹肌溶解（骨骼肌退化）、溶血、药物和外源性毒素的产物。其中许多化合物通过产生活性氧 (ROS) 来激活凋亡核酸内切酶，从而导致急性肾损伤 (AKI)。由此产生的急性肾衰竭（AKF）是一种危及生命的疾病，需要血液透析或肾移植。该提案是之前的研究由 VA 优异评审资助资助。先前项目中的具体目标已经实现，新目标是这些目标的逻辑延伸。先前的研究结果表明，凋亡核酸内切酶G（EndoG）在介导肌红蛋白尿性AKI中的重要性要复杂得多，不仅限于DNA断裂，而且在某些情况下，与最初所接受的完全相反。本提议基于我们最近的意外观察，即肌红蛋白尿性 AKI 是由 EndoG 调节的凋亡脱氧核糖核酸酶 I (DNase I) 介导的。在这项研究之前，尚未描述过另一种核酸内切酶对另一种核酸内切酶的调节作用，并且 EndoG 被认为是 DNA 断裂凋亡核酸内切酶之一。与此相反，我们发现当 EndoG 因较晚或更严重的损伤而激活时，它会使 DNase I 失活，从而防止损伤。因此，在肾脏中，EndoG 充当细胞保护酶而不是细胞毒性酶。我们假设肌红蛋白尿性 AKI 可以通过诱导 EndoG 介导的 DNase I 失活或在损伤之前和/或之后抑制 DNase I 的表达或活性来预防。我们的具体目标如下。在目标 1 中，我们将评估基于天然 DNase I 和选择性剪接 DNase I 的治疗方法，以改善肌红蛋白尿性肾小管细胞损伤和 AKI。在目标 2 中，我们计划确定如何利用 EndoG 介导的 DNase I 失活来减弱肌球尿性 AKI。目标 3 将使用我们新的高通量技术来筛选化学库，寻找适用于治疗肌红蛋白尿性 AKI 的新型 DNase I 抑制剂。对退伍军人医疗保健的潜在影响。这些研究的成功完成可能会导致开发新的治疗工具来预防或改善肌红蛋白尿性 AKI。其中一些药物具有很强的转化价值，因为即使在肾损伤后施用它们也能发挥作用，而另一些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数量。