Autophagy and Drug-Induced Liver Injury

自噬和药物性肝损伤

基本信息

批准号：
10378131
负责人：
Wen-Xing Ding
金额：
$ 34.43万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-25 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378131
关键词：
Acetaminophen Acetylcysteine Acute Liver Failure Alcoholic Liver Diseases Animal Genetics Animal Model Attenuated Autophagocytosis Binding Biogenesis Cell Death Cellular Stress Clinic Clinical Country DNA Fragmentation Data Degradation Pathway Dependovirus Etiology Excision FDA approved FRAP1 gene Foundations Funding Generations Genetic Genetic Transcription Glutathione Goals Guanosine Triphosphate Phosphohydrolases Hepatocyte Hepatotoxicity High Fat Diet Homeostasis Human Imines Impairment Injury Knockout Mice Knowledge Liver Liver Failure Liver Regeneration Lysosomes Mediating Mitochondria Mitochondrial Proteins Molecular Monitor Mus Natural regeneration Necrosis Organ Outcome Pathway interactions Patients Pharmacology Phase Phosphorylation Phosphotransferases Proteins Raptors Reactive Oxygen Species Recovery Research Role Signal Transduction TSC1 gene Testing Therapeutic Therapeutic Intervention Transcriptional Activation United States acetaminophen overdose acetaminophen-induced liver injury acute liver injury adduct base drug candidate drug development drug induced liver injury gain of function improved innovation liver injury mitochondrial dysfunction mouse model new therapeutic target novel overexpression oxidant stress para-benzoquinone prevent programs repaired response therapeutic target therapeutically effective tool transcription factor

项目摘要

PROJECT SUMMARY / ABSTRACT Acetaminophen (APAP) hepatotoxicity is the most frequent cause of acute liver failure of any etiology in the United States. However, no effective therapeutic strategies for APAP-induced liver injury are currently available, especially for late presenting patients. It is well known that after APAP overdose, N-acetyl-p- benzoquinone imine (NAPQI), the reactive metabolite of APAP, binds to cellular and mitochondrial proteins to form APAP-protein adducts (APAP-AD) following the depletion of cellular glutathione, which triggers mitochondrial dysfunction, oxidant stress and subsequent necrosis. In our previous funding cycle, we demonstrated that activation of autophagy, a cellular adaptive response of lysosomal degradation pathway, protects against APAP-induced liver injury by removing APAP-AD and damaged mitochondria. Liver is a very dynamic organ that has the capacity to repair and regenerate after injury. We also demonstrated that increased mitochondrial biogenesis can improve liver regeneration and recovery from APAP-induced liver injury. Importantly, our preliminary data showed that the transcription factor EB (TFEB), a master regulator that governs both the biogenesis of lysosomes for autophagy and mitochondria for regeneration, was impaired during the course of APAP-induced liver injury. Therefore, the major goal of this competitive R01 renewal is to understand the molecular mechanisms by which APAP impairs TFEB signaling in the liver. Our central hypothesize is that activation of TFEB will lead to increased biogenesis of both lysosomes and mitochondria that inhibits the progression of APAP-induced liver injury and promotes the liver regeneration. Two specific aims are proposed: 1) determine the mechanisms by which APAP impairs TFEB-mediated biogenesis of lysosomes and mitochondria in hepatocytes; and 2) determine the mechanism(s) by which TFEB promotes the recovery from APAP-induced liver injury by increased biogenesis of lysosomes and mitochondria. The proposed research is innovative in the concept that a transcription program that governs both the autophagy-lysosomal pathway and mitochondrial biogenesis is impaired in APAP-induced liver injury. We will utilize novel genetic animal models such as liver-specific TFEB KO mice, and adeno-associated virus- mediated overexpression of TFEB and PGC-1α approaches to specifically investigate the role of TFEB and PGC-1α in autophagic removal of damaged mitochondrial and enhancing new mitochondria biogenesis in reversal of APAP-induced liver injury. Moreover, we will also utilize the newly developed new molecular tools to accurately monitor and quantify the zonated changes of mitophagy and mitochondrial biogenesis in mouse livers after APAP. Results from our proposed study will lead to the in-depth understanding of the TFEB- mediated cellular adaptive response in promoting autophagic degradation of damaged mitochondria and mitochondrial biogenesis in the reversal of APAP-induced liver injury. Ultimately, such knowledge has the potential of identifying novel therapeutic targets for treating APAP-induced liver injury and acute liver failure.

项目概要/摘要对乙酰氨基酚 (APAP) 肝毒性是所有病因中急性肝衰竭的最常见原因。然而，美国目前尚无针对APAP引起的肝损伤的有效治疗策略。众所周知，APAP 过量后，N-乙酰基-p- 苯醌亚胺 (NAPQI) 是 APAP 的反应性代谢产物，与细胞和线粒体蛋白结合，细胞谷胱甘肽耗尽后形成 APAP-蛋白加合物 (APAP-AD)，从而触发在我们之前的资助周期中，我们研究了线粒体功能障碍、氧化应激和随后的坏死。自噬的激活，溶酶体降解途径的细胞适应性反应，通过去除 APAP-AD 和受损的线粒体来防止 APAP 引起的肝损伤。我们还证明了损伤后具有修复和再生能力的动态器官。线粒体生物发生可以改善肝再生和 APAP 引起的肝损伤的恢复。重要的是，我们的初步数据表明转录因子 EB (TFEB)，一个主调节因子，控制自噬溶酶体和再生线粒体的生物发生，受到损害因此，R01 更新的主要目标是在 APAP 引起的肝损伤过程中。了解 APAP 损害肝脏中 TFEB 信号传导的分子机制。正在研究 TFEB 的激活将导致溶酶体和线粒体的生物合成增加抑制 APAP 引起的肝损伤的进展并促进肝再生。提出了两个具体目标：1）确定 APAP 损害 TFEB 介导的机制肝细胞中溶酶体和线粒体的生物合成；2) 确定 TFEB 的机制；通过增加溶酶体的生物发生促进 APAP 诱导的肝损伤的恢复拟议的研究在控制转录程序的概念上具有创新性。在 APAP 诱导的肝损伤中，自噬-溶酶体途径和线粒体生物合成均受到损害。我们将利用新型遗传动物模型，例如肝脏特异性 TFEB KO 小鼠和腺相关病毒 - 介导的 TFEB 和 PGC-1α 过表达方法专门研究 TFEB 和 PGC-1α 的作用 PGC-1α 在自噬去除受损线粒体并增强新线粒体生物合成中的作用此外，我们还将利用新开发的新分子工具来逆转 APAP 引起的肝损伤。准确监测和量化小鼠线粒体自噬和线粒体生物发生的分区变化我们提出的研究结果将有助于深入了解 TFEB- 介导细胞适应性反应，促进受损线粒体的自噬降解，线粒体生物发生在逆转 APAP 诱导的肝损伤中的作用最终得到了证实。确定治疗 APAP 引起的肝损伤和急性肝衰竭的新治疗靶点的潜力。

项目成果

期刊论文数量（72）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The role of the c-Jun N-terminal kinases 1/2 and receptor-interacting protein kinase 3 in furosemide-induced liver injury.

c-Jun N 末端激酶 1/2 和受体相互作用蛋白激酶 3 在呋塞米诱导的肝损伤中的作用。

DOI：
发表时间：
2015-05
期刊：
影响因子：
0
作者：
McGill, Mitchell R;Du, Kuo;Xie, Yuchao;Bajt, Mary Lynn;Ding, Wen;Jaeschke, Hartmut
通讯作者：
Jaeschke, Hartmut

Benzyl alcohol protects against acetaminophen hepatotoxicity by inhibiting cytochrome P450 enzymes but causes mitochondrial dysfunction and cell death at higher doses.

苯甲醇通过抑制细胞色素 P450 酶来防止对乙酰氨基酚的肝毒性，但较高剂量时会导致线粒体功能障碍和细胞死亡。

DOI：
发表时间：
2015-12
期刊：
影响因子：
0
作者：
Du, Kuo;McGill, Mitchell R;Xie, Yuchao;Jaeschke, Hartmut
通讯作者：
Jaeschke, Hartmut

Mitochondria-targeted antioxidant Mito-Tempo protects against acetaminophen hepatotoxicity.

线粒体靶向抗氧化剂 Mito-Tempo 可防止对乙酰氨基酚的肝毒性。

DOI：
发表时间：
2017-02
期刊：
影响因子：
6.1
作者：
Du, Kuo;Farhood, Anwar;Jaeschke, Hartmut
通讯作者：
Jaeschke, Hartmut

Loss of hepatic DRP1 exacerbates alcoholic hepatitis by inducing megamitochondria and mitochondrial maladaptation.

肝脏 DRP1 的缺失会诱导巨线粒体和线粒体适应不良，从而加剧酒精性肝炎。

DOI：
发表时间：
2023-01-01
期刊：
影响因子：
0
作者：
Ma, Xiaowen;Chen, Allen;Melo, Luma;Clemente;Chao, Xiaojuan;Ahmadi, Ali Reza;Peiffer, Brandon;Sun, Zhaoli;Sesaki, Hiromi;Li, Tiangang;Wang, Xiaokun;Liu, Wanqing;Bataller, Ramon;Ni, Hong;Ding, Wen
通讯作者：
Ding, Wen

SQSTM1/p62 and Hepatic Mallory-Denk Body Formation in Alcohol-Associated Liver Disease.

SQSTM1/p62 和酒精相关性肝病中的肝 Mallory-Denk 体形成。