Modulating purine metabolism to treat kidney injury in sepsis.

调节嘌呤代谢以治疗脓毒症肾损伤。

基本信息

批准号：
9478173
负责人：
Takashi Hato
金额：
$ 15.66万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
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/9478173
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 Gene Targeting Genes Goals Guanosine Health Immunosuppression Indiana Inflammation Injury Isotopes Kidney Label Mass Spectrum Analysis Mediating Medicine Mentors Metabolic Pathway Microdissection Mission Modeling Molecular Nephrology Oxidative Stress Pathway interactions Patients Phagocytosis Phenotype Physicians Preventive Intervention 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 Treatment Efficacy 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 professor protective effect purine metabolism septic targeted treatment tool transcriptomics

项目摘要

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.

项目概要/摘要候选人和环境：Takashi Hato，医学博士是医学部的助理教授印第安纳大学医学院肾脏病学。申请人的长期目标是成为一名医生科学家，专注于发现急性肾损伤的靶向疗法。他的K08的主要目标该提案旨在深入了解嘌呤代谢在脓毒症引起的急性肾损伤中的作用。这申请人计划在未来的研究中扩展工作，最终目标是利用这种代谢控制能量的途径和第二信使系统以保护肾脏。 Pierre Dagher 博士，教授医学，是一位卓有成就的医师科学家，专门研究急性肾损伤。达格博士一直是申请人自肾脏病专科培训以来的主要导师，并将在期间担任主要导师本次获奖的历程。研究：败血症仍然是住院患者死亡的主要原因。成活率进一步当脓毒症并发急性肾损伤时，病情会恶化。迫切需要识别新颖的治疗脓毒症及其严重后遗症的治疗方法。对于这项提议，Hato 博士和他的团队进行了无偏见的代谢组学和转录组学分析，发现嘌呤代谢严重脓毒症的肾脏紊乱。脓毒症导致嘌呤核苷显着消耗，最显着的是鸟苷。他们的初步工作还表明，外源鸟苷补充可以调节多个基因参与嘌呤代谢途径并限制肾损伤。的有益作用脓毒症中的鸟苷尚不清楚。因此，本应用程序的主要目标是研究鸟苷介导的肾脏保护机制。他们假设鸟苷的保护作用通过在基因水平上对肾嘌呤代谢进行正重编程来治疗。工具组合将使用包括活体显微镜、体内 siRNA 技术、显微切割和同位素示踪技术在细胞和分子水平上研究鸟苷的作用机制，而不影响体内意义。