Autophagy in liver injury

肝损伤中的自噬

基本信息

批准号：
7778923
负责人：
Jae-Sung Kim
金额：
$ 34.65万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-05 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7778923
关键词：
1-Phosphatidylinositol 3-Kinase Abbreviations Abdomen Adenoviruses Anoxia Apoptosis Attention Attenuated Autophagocytosis Autophagosome Bioenergetics Blood flow Brain Calpain Cardiovascular Surgical Procedures Cell Death Cell physiology Cells Cessation of life Clinical Trials Communities Compartment syndromes Complication Cyclosporine Cyclosporins Data Etiology Eukaryotic Initiation Factors Event Excision Extracorporeal Circulation Figs - dietary Genetic Goals Green Fluorescent Proteins Heart Hemorrhagic Shock Hepatic Hepatocyte Histologic Hydrolysis Image Impairment In Vitro Injury Injury to Liver Intervention Investigation Ischemia Light Liver Liver Disease Shock Liver Liver Dysfunction Liver Failure Liver diseases Measures Mediating Microscopic Microscopy Microtubule-Associated Proteins Microtubules Mitochondria Modeling Monitor Morbidity - disease rate Mus Necrosis Normal Range Operative Surgical Procedures Pathway interactions Patients Permeability Physiological Postoperative Period Process Propidium Diiodide Protein Isoforms Protein Kinase Proteins Quality Control Rattus Reactive Oxygen Species Recovery Recycling Reperfusion Injury Reperfusion Therapy Reporting Research Role Simulate Sirolimus Testing Therapeutic Tissues Transplantation Trauma Viral Warm Ischemia cell injury chelation design hepatic necrosis human FRAP1 protein improved in vivo in vivo Model innovation insight liver function liver imaging liver transplantation mitochondrial autophagy mitochondrial dysfunction mortality novel novel therapeutic intervention overexpression prevent public health relevance research study restoration tetramethylrhodamine methyl ester translational study tumor xanthate D609

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial dysfunction is the major mechanism precipitating ischemia/reperfusion (I/R) injury which commonly occurs during liver surgery, trauma, hemorrhagic shock and liver transplantation. Mitochondrial autophagy (mitophagy) is the only cellular process that selectively removes abnormal mitochondria. The contribution of mitophagy to liver injury after warm ischemia is unknown. The goal of this study is to elucidate the mechanisms underlying lethal I/R injury to liver and to develop therapeutic strategies to improve liver function after I/R. In preliminary studies, we observed the loss of Atg7 and Beclin-1, key mitophagy proteins, after I/R. We have shown that Ca2+ overloading after I/R stimulates calpain isoform-2 and that activated calpain-2 degrades Atg7 and Beclin-1. Suppression of mitophagy protein depletion prevents onset of the mitochondrial permeability transition (MPT), hepatocellular necrosis and apoptosis, and protects mitochondrial function after I/R. Furthermore, we noted that loss of mitophagy proteins occurs in an in vivo model of hepatic I/R in mice, concomitant with mitochondrial depolarization and cell death. We propose that I/R impairs mitophagy, which in turn leads to accumulation of dysfunctional mitochondria and ultimately hepatic failure. Therefore, restoration or enhancement of mitophagy in ischemic liver will promote the clearance of dysfunctional mitochondria and consequently ameliorate liver dysfunction after reperfusion. Our principle hypothesis is that Ca2+ overloading causes increased calpain-2 activity that subsequently results in hydrolyzation of key mitophagy proteins leading to impaired mitophagy and MPT-dependent hepatocyte death after I/R. These studies provide critical mechanistic insights into lethal I/R injury to liver, and will establish novel therapeutic approaches for improving I/R-mediated liver failure. PUBLIC HEALTH RELEVANCE: Impairment of blood flow causes a tissue ischemia and recovery of blood flow causes reperfusion injury to liver. Ischemia/reperfusion (I/R) injury is a causative factor of morbidity and mortality during liver resection, hemorrhagic shock, cardiovascular surgery with extracorporeal circulation, transplantation and abdominal compartment syndrome. I/R injury remains a fundamental complication of hepatic surgery, and patients with preexisting liver diseases that often require inflow occlusion are more likely to develop severe postoperative I/R injury. Better understanding of the mechanisms underlying ischemia/reperfusion injury would establish novel therapeutic approaches for improving liver function after liver surgery.

描述（由申请人提供）：线粒体功能障碍是沉淀缺血/再灌注（I/R）损伤的主要机制，通常发生在肝手术，创伤，出血性休克和肝移植期间。线粒体自噬（线粒体）是唯一选择性去除线粒体异常的细胞过程。线粒体对温暖缺血后肝损伤的贡献尚不清楚。这项研究的目的是阐明肝脏致死I/R损伤的机制，并制定治疗策略以改善I/R后提高肝功能。在初步研究中，我们观察到I/R之后的ATG7和Beclin-1，关键线索蛋白的丧失。我们已经表明，I/R后Ca2+过载刺激Calpain同工型-2，并且激活Calpain-2降解ATG7和Beclin-1。抑制线粒体蛋白的耗竭可防止线粒体通透性转变（MPT），肝细胞坏死和凋亡的发作，并在I/R之后保护线粒体功能。此外，我们注意到，线粒体蛋白的损失发生在小鼠的肝I/R的体内模型中，与线粒体去极化和细胞死亡有关。我们建议I/R会损害线粒体，从而导致线粒体功能失调并最终导致肝衰竭。因此，缺血性肝脏中线粒体的恢复或增强将促进线粒体功能障碍的清除，从而改善再灌注后减轻肝功能障碍。我们的原理假设是Ca2+过载导致CALPAIN-2活性增加，随后导致关键的线粒体蛋白水解导致I/R后的线粒能和MPT依赖性肝细胞死亡受损。这些研究提供了对肝脏致命I/R损伤的关键机理见解，并将建立新的治疗方法来改善I/R介导的肝衰竭。公共卫生相关性：血流损害会导致组织缺血，而血流的恢复会导致肝脏再灌注损伤。缺血/再灌注（I/R）损伤是肝切除期间发病率和死亡率的病因，出血性休克，心血管手术，具有体外循环，移植和腹部隔室综合征。 I/R损伤仍然是肝手术的根本并发症，并且患有经常需要流入闭塞的肝病患者更有可能造成严重的术后I/R损伤。更好地了解缺血/再灌注损伤的机制将建立新的治疗方法，以改善肝脏手术后肝功能。