BLRD Research Career Scientist Award Application

PI是细胞毒(凋亡)DNA酶、DNA内切酶方面的专家。尽管他们是“细胞凋亡者” 名称，这些酶负责任何机制的最终和不可逆转的细胞死亡后 组织损伤包括药物效应、疾病或创伤在内的组织损伤DNA酶通过将细胞碎片化来杀死细胞 损伤后的DNA。PI的团队确定了参与死前DNA的内切酶 急性肾毒性(顺铂、甘油)中毒或缺氧时肾小管上皮细胞的碎裂 衰竭、中毒性肝损伤(扑热息痛、酒精、碳纳米管)、全身伽马 在辐射诱导的乳腺、前列腺或黑色素瘤细胞死亡过程中 抗癌药物(多西紫杉醇、依托泊苷、喜树碱、顺铂、环磷酰胺和新 开发的抗癌剂)。这些发现强烈地表明，抑制或失活 在两种最活跃的内切酶中，DNase I或endog在不同的细胞死亡中具有保护作用 伤害和毒性的模型。该组织还有证据表明，这些酶属于 以前未知的网络，通过DNA断裂进行通信，并在其中激活 一个核酸内切酶的缺失可能导致整个网络的激活，随后是DNA片段化 以及不可逆转的细胞死亡。首个药理良好、无毒的核酸内切酶抑制剂 该团队开发的药物很有希望成为潜在的通用细胞保护药物 适用于调节人体疾病过程中的细胞死亡，包括器官衰竭、癌症 和动脉粥样硬化，以及药物的副作用。PI的研究发表在高度- 评价期刊包括《美国肾脏病学会杂志》、《欧洲心脏杂志》、《自然》 通讯、肝病、动脉粥样硬化血栓形成和血管生物学、肾脏 国际，细胞死亡和分化，美国生理学杂志，科学报告， 人类分子遗传学，以及其他。这些研究与退伍军人管理局的医疗保健高度相关 因为器官损伤在退伍军人、军人和老年人中很常见。的研究 核酸内切酶抑制剂有望成为急性胰腺炎的通用无毒保护剂。 各种器官损伤，既可在军事行动中应用，也可用于 改善退伍军人因疾病引起的器官损伤。因此，这些研究的结果 由PI领导的可能最终拯救人类生命，改善退伍军人的健康和福祉， 并减少退伍军人和普通人口中的残疾人数。

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.