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在危险武器、病原体、