BLRD Research Career Scientist Award Application

BLRD 研究职业科学家奖申请

• 批准号: 10589265
• 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: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2027-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589265
• 关键词: Acetaminophen; Acute; Acute Kidney Failure; Acute Renal Failure with Renal Papillary Necrosis; Acute myocardial infarction; Affect; Alcohols; American; Antineoplastic Agents; Apoptotic; Area; Atherosclerosis; Award; Biology; Blood Vessels; Breast; Camptothecin; Carbon Nanotubes; Cardiovascular Diseases; Cell Death; Cell Death Induction; Cell Differentiation process; Cell Membrane Permeability; Cells; Cessation of life; Chemical Injury; Chronic Kidney Failure; Cisplatin; Communication; Cytoprotective Agent; DNA; DNA Fragmentation; Data; Deoxyribonuclease I; Deoxyribonucleases; Disease; Drug Side Effects; Drug or Chemical; Elderly; Endothelial Cells; Enzymes; Epithelium; Etoposide; European; Funding; General Population; Genomic DNA; Glycerol; Grant; Grant Review; Health; Healthcare; Heart; Hemodialysis; Hepatology; Homeostasis; Hospitalization; Human; Human Resources; Hypoxia; Individual; Injury; International; Ions; Journals; Kidney; Kidney Failure; Low-Density Lipoproteins; Malignant Neoplasms; Measures; Mechanics; Mediating; Military Personnel; Modeling; Molecular Genetics; Muscle; Names; Nature; Nephrology; Nuclear Envelope; Organ; Organ failure; Patients; Personal Satisfaction; Pharmaceutical Preparations; Physiology; Poisoning; Population; Prostate; Protective Agents; Proteins; Publishing; Radiation; Reporting; Research; Research Personnel; Risk; Risk Factors; Role; Scientist; Societies; Thrombosis; Toxic Hepatitis; Toxic effect; Trauma; Tubular formation; United States Department of Agriculture; United States National Institutes of Health; Veterans; cancer cell; cardiovascular risk factor; career; cell injury; cell killing; cytotoxic; disability; docetaxel; endonuclease; follow-up; gamma irradiation; human disease; improved; inhibitor; melanoma; military operation; mortality; operation; organ injury; pharmacologic; sound; tissue injury

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.

PI是细胞毒性（凋亡）DNA酶和DNA内切酶方面的专家。尽管他们的“凋亡” 名称，这些酶负责最终和不可逆的细胞死亡后的任何机制 组织损伤，包括药物作用、疾病或创伤。脱氧核糖核酸酶通过将细胞的 受伤后的DNA PI的团队鉴定了参与死前DNA的核酸内切酶 在毒性（顺铂、甘油）或缺氧急性肾损伤过程中肾小管上皮细胞断裂 衰竭、中毒性肝损伤（对乙酰氨基酚、酒精、碳纳米管）、全身伽马 辐射以及乳腺癌、前列腺癌或黑色素瘤癌细胞在辐射诱导的细胞死亡期间 抗癌药物（多西他赛、依托泊苷、喜树碱、顺铂、环磷酰胺，以及新的 开发的抗癌剂）。这些发现有力地表明， 两种最具活性的核酸内切酶，DNA酶I或EndoG，在各种细胞中对细胞死亡具有保护作用。 损伤和毒性模型。该小组还有证据表明，这些酶属于 以前未知的网络，通过DNA断裂进行通信，并且在其中激活 一种核酸内切酶的激活可能导致整个网络的激活，随后是DNA片段化 以及不可逆的细胞死亡第一个可靠、无毒的核酸内切酶抑制剂 由该团队开发的药物作为潜在的通用细胞保护药物具有很大的前景 可用于调节人类疾病，包括器官衰竭、癌症 动脉粥样硬化以及药物的副作用。PI的研究发表在高度- 评级期刊包括Journal of American Society of Nephrology、European Heart J、Nature 通讯，肝病学，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， 人类分子遗传学及其他这些研究与VA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希望成为急性胰腺炎的通用无毒保护剂， 各种器官损伤，可用于军事行动， 改善退伍军人疾病引起的器官损伤。因此，研究结果 由PI领导的项目可能最终拯救人类生命，改善退伍军人的健康和福祉， 减少退伍军人和普通民众的残疾人数。