Autophagy in liver injury

肝损伤中的自噬

基本信息

批准号：
8212405
负责人：
Jae-Sung Kim
金额：
$ 30.79万
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/8212405
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 Genetic Goals Green Fluorescent Proteins Health Heart Hemorrhagic Shock Hepatic Hepatocyte Histologic 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 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（申请人提供）：线粒体功能障碍是引发缺血/再灌注（I/R）损伤的主要机制，这种损伤通常发生在肝脏手术、创伤、失血性休克和肝移植过程中。线粒体自噬（mitophagy）是唯一选择性清除异常线粒体的细胞过程。线粒体自噬对热缺血后肝损伤的影响尚不清楚。本研究的目的是阐明缺血再灌注对肝脏造成致命性损伤的机制，并制定改善缺血再灌注后肝功能的治疗策略。在初步研究中，我们观察到缺血再灌注后关键线粒体自噬蛋白 Atg7 和 Beclin-1 的丢失。我们已经证明 I/R 后 Ca2+ 超载会刺激 calpain isoform-2，并且激活的 calpain-2 会降解 Atg7 和 Beclin-1。抑制线粒体自噬蛋白消耗可防止线粒体通透性转变 (MPT)、肝细胞坏死和细胞凋亡的发生，并保护 I/R 后的线粒体功能。此外，我们注意到，在小鼠肝缺血再灌注的体内模型中，线粒体自噬蛋白的丢失发生，并伴随着线粒体去极化和细胞死亡。我们认为 I/R 会损害线粒体自噬，进而导致功能失调的线粒体积聚并最终导致肝衰竭。因此，缺血肝脏中线粒体自噬的恢复或增强将促进功能障碍的线粒体的清除，从而改善再灌注后的肝功能障碍。我们的主要假设是 Ca2+ 超载导致 calpain-2 活性增加，随后导致关键线粒体自噬蛋白水解，导致 I/R 后线粒体自噬受损和 MPT 依赖性肝细胞死亡。这些研究为缺血再灌注对肝脏造成的致命损伤提供了重要的机制见解，并将建立改善缺血再灌注介导的肝衰竭的新治疗方法。公共卫生相关性：血流受损会导致组织缺血，血流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、失血性休克、体外循环心血管手术、移植和腹腔间隔室综合征期间发病和死亡的一个致病因素。 I/R 损伤仍然是肝手术的基本并发症，患有先前存在肝病且通常需要阻塞流入的患者更有可能发生严重的术后 I/R 损伤。更好地了解缺血/再灌注损伤的机制将为肝脏手术后改善肝功能建立新的治疗方法。