BLRD Research Career Scientist Award Application

点击翻译按钮获取中文摘要

The PI is an expert in cytotoxic (apoptotic) DNases, DNA endonucleases. Despite their “apoptotic” name, these enzymes are responsible for final and irreversible cell death of any mechanism after a tissue injury including drug effects, diseases, or traumas. DNases kill cells by fragmenting their DNA after injury. The PI’s team identifies the endonucleases that participate in premortem DNA fragmentation in kidney tubular epithelium during toxic (cisplatin, glycerol) or hypoxic acute renal failure, toxic liver injury (acetaminophen, alcohol, carbon nanotubes), total body gamma irradiation, and in breast, prostate, or melanoma cancer cells during cell death induced by anticancer drugs (docetaxel, etoposide, camptothecin, cisplatin, cyclophosplamide, and newly developed anticancer agents). These findings strongly indicate that the inhibition or inactivation of two most active endonucleases, DNase I or EndoG, is protective against cell death in various models of injury and toxicity. The group also has evidence that these enzymes belong to previously unknown network, which communicate through DNA breaks, and in which an activation of one endonuclease may lead to activation of the entire network, followed by DNA fragmentation and irreversible cell death. First pharmacologically sound, non-toxic endonuclease inhibitors developed by the team have a great promise as potentially universal cytoprotective drugs applicable for modulation of cell death during human diseases, including organ failures, cancer and atherosclerosis, as well as side effects of drugs. The PI’s studies are published in highly- rated journals including Journal of American Society of Nephrology, European Heart J, Nature Communications, Hepatology, Atherosclerosis Thrombosis and Vascular Biology, Kidney International, Cell Death and Differentiation, American Journal of Physiology, Scientific Reports, Human Molecular Genetics, and others. These studies are highly relevant to the VA healthcare because organ injuries are common in Veterans, military personnel and elderly. The studies of endonuclease inhibitors have a promise of being universal non-toxic protective agents of acute organ injuries of various kinds, which could be applied both during military operations and to ameliorate organ injuries induced by diseases in Veterans. Therefore, the results of the studies led by the PI may eventually save human lives, improve the health and wellbeing of Veterans, and decrease the number of disabilities among Veterans and in the general population.