Modulating purine metabolism to treat kidney injury in sepsis.

调节嘌呤代谢以治疗脓毒症肾损伤。

• 批准号: 10155474
• 负责人: Takashi Hato
• 金额: $ 12.93万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155474
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Animal Model; Animals; Attenuated; Award; Cause of Death; Cyclic GMP; Data; Degradation Pathway; Development; Disease; Endotoxins; Environment; Enzymes; Fellowship; Future; Gene Expression; Genes; Goals; Guanosine; Health; Immunosuppression; Indiana; Inflammation; Injury; Injury to Kidney; Isotopes; Kidney; Label; Mass Spectrum Analysis; Mediating; Medicine; Mentors; Metabolic Pathway; Microdissection; Mission; Modeling; Molecular; Nephrology; Oxidative Stress; Pathway interactions; Patients; Phagocytosis; Phenotype; Physicians; Property; Public Health; Purine Nucleosides; Purines; Reactive Oxygen Species; Research; Role; Scientist; Second Messenger Systems; Sepsis; Signaling Molecule; Small Interfering RNA; Supplementation; Supportive care; Survival Rate; Technology; Testing; Therapeutic; Therapeutic Intervention; Training; Tubular formation; United States National Institutes of Health; Universities; Work; Xanthine Oxidase; base; cell type; in vivo; insight; intravital microscopy; knock-down; medical schools; metabolomics; mortality; novel therapeutic intervention; preconditioning; prevent; preventive intervention; professor; protective effect; purine metabolism; septic; targeted treatment; therapeutically effective; tool; transcriptomics

Project Summary/Abstract Candidate and environment: Takashi Hato, MD is Assistant Professor of Medicine in the Division of Nephrology at Indiana University School of Medicine. The applicant's long-term goal is to become a physician scientist with a focus on the discovery of targeted therapies for acute kidney injury. The primary goal of his K08 proposal is to provide insight into the role of purine metabolism in sepsis-induced acute kidney injury. The applicant plans on extending the work in his future studies with the ultimate goal to harness this metabolic pathway to control energy and second messenger system for renal protection. Dr. Pierre Dagher, Professor of Medicine, is an accomplished physician scientist specializing in acute kidney injury. Dr. Dagher has been the applicant's primary mentor since his nephrology fellowship training and will serve as the primary mentor during the course of this award. Research: Sepsis remains the leading cause of death in hospitalized patients. The survival rate further deteriorates when sepsis is complicated by acute kidney injury. There is a critical need to identify novel therapeutic approaches to treat sepsis and its grave sequelae. For this proposal, Dr. Hato and his team have performed unbiased metabolomics and transcriptomics analyses and found that purine metabolism is severely deranged in the septic kidneys. Sepsis resulted in significant depletion of purine nucleosides, most notably guanosine. Their preliminary work also revealed that exogenous guanosine supplementation could modulate multiple genes involved in the purine metabolism pathway and limit kidney injury. The beneficial role of guanosine in sepsis is largely unknown. It is therefore the primary goal of this application to investigate the mechanisms of guanosine-mediated renal protection. They hypothesize that the protective effects of guanosine are medicated by positive reprograming of renal purine metabolism at the gene level. A combination of tools will be used including intravital microscopy, in vivo siRNA technology, microdissection and isotope tracing to investigate the mechanisms of guanosine action at the cellular and molecular levels without compromising in vivo significance.

项目摘要/摘要 候选人与环境：医学博士Takashi Hato是医学助理教授 印第安纳大学医学院的肾脏病。申请人的长期目标是成为医生 科学家专注于发现针对急性肾脏损伤的靶向疗法。他的K08的主要目标 提案是为嘌呤代谢在败血症引起的急性肾脏损伤中的作用提供见解。这 申请人计划在未来的研究中扩展工作，以利用这种代谢的最终目标 控制能源和第二信使系统的途径。 Pierre Dagher博士，教授 医学是一位专门从事急性肾脏损伤的医师科学家。 Dagher博士一直是 申请人的主要导师以来他的肾脏学奖学金培训，并将在 这个奖项的课程。 研究：败血症仍然是住院患者死亡的主要原因。进一步的存活率 当急性肾脏损伤使败血症复杂时，会恶化。识别小说的迫切需要 治疗败血症及其严重的后遗症的治疗方法。对于此建议，Hato博士和他的团队有 进行了公正的代谢组学和转录组学分析，发现嘌呤代谢严重 在化粪池肾脏中被扰乱。败血症导致嘌呤核苷的显着耗竭，最著名的是 鸟嘌呤。他们的初步工作还表明，补充外源鸟嘌呤可以调节 多个基因参与嘌呤代谢途径并限制肾脏损伤。有益的作用 脓毒症中的鸟嘌呤在很大程度上是未知的。因此，这是该应用程序的主要目标 鸟苷介导的肾脏保护的机制。他们假设鸟嘌呤的保护作用 通过在基因水平上肾嘌呤代谢的阳性重编程来药物。工具的组合 将使用包括浸润显微镜，体内siRNA技术，显微解剖和同位素追踪到 研究在细胞和分子水平上作用的机制，而不会损害 体内意义。