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:
  • 金额:
    $ 34.43万
  • 依托单位:
  • 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

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.
项目摘要/摘要

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 thrombopoietin mimetic JNJ-26366821 reduces the late injury and accelerates the onset of liver recovery after acetaminophen-induced liver injury in mice.
血小板生成素模拟物 JNJ-26366821 可减少对乙酰氨基酚诱导的小鼠肝损伤后的晚期损伤并加速肝脏恢复。
  • DOI:
    10.1007/s00204-024-03725-2
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    6.1
  • 作者:
    Adelusi,OlamideB;Akakpo,JephteY;Eichenbaum,Gary;Sadaff,Ejaz;Ramachandran,Anup;Jaeschke,Hartmut
  • 通讯作者:
    Jaeschke,Hartmut
SQSTM1/p62 and Hepatic Mallory-Denk Body Formation in Alcohol-Associated Liver Disease.
  • DOI:
    10.1016/j.ajpath.2023.02.015
  • 发表时间:
    2023-10
  • 期刊:
  • 影响因子:
    6
  • 作者:
    Qian, Hui;Ding, Wen-Xing
  • 通讯作者:
    Ding, Wen-Xing
Inhibitor of apoptosis signal-regulating kinase 1 protects against acetaminophen-induced liver injury.
  • DOI:
    10.1016/j.taap.2015.03.019
  • 发表时间:
    2015-07-01
  • 期刊:
  • 影响因子:
    3.8
  • 作者:
    Xie, Yuchao;Ramachandran, Anup;Breckenridge, David G.;Liles, John T.;Lebofsky, Margitta;Farhood, Anwar;Jaeschke, Hartmut
  • 通讯作者:
    Jaeschke, Hartmut
Structure, Regulation and Function of Gap Junctions in Liver.
  • DOI:
    10.3109/15419061.2016.1151875
  • 发表时间:
    2015-04
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Willebrords J;Crespo Yanguas S;Maes M;Decrock E;Wang N;Leybaert L;da Silva TC;Veloso Alves Pereira I;Jaeschke H;Cogliati B;Vinken M
  • 通讯作者:
    Vinken M
Role of autophagy in alcohol and drug-induced liver injury.
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Wen-Xing Ding其他文献

Wen-Xing Ding的其他文献

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{{ truncateString('Wen-Xing Ding', 18)}}的其他基金

Novel mechanisms of regulating endoplasmic reticulum homeostasis in alcoholic pancreatitis
调节酒精性胰腺炎内质网稳态的新机制
  • 批准号:
    10742433
  • 财政年份:
    2023
  • 资助金额:
    $ 34.43万
  • 项目类别:
Mechanisms regulating autophagy in alcohol-induced liver injury
酒精性肝损伤中自噬的调节机制
  • 批准号:
    10468416
  • 财政年份:
    2022
  • 资助金额:
    $ 34.43万
  • 项目类别:
Mechanisms regulating autophagy in alcohol-induced liver injury
酒精性肝损伤中自噬的调节机制
  • 批准号:
    10612977
  • 财政年份:
    2022
  • 资助金额:
    $ 34.43万
  • 项目类别:
Mechanisms of Impaired Lysosomal Biogenesis and Autophagy in Alcohol-Associated Alzheimer's Disease
酒精相关阿尔茨海默氏病溶酶体生物发生和自噬受损的机制
  • 批准号:
    10266178
  • 财政年份:
    2020
  • 资助金额:
    $ 34.43万
  • 项目类别:
Mechanisms of Impaired Lysosomal Biogenesis and Autophagy in Alcohol-Associated Alzheimer's Disease
酒精相关阿尔茨海默氏病溶酶体生物发生和自噬受损的机制
  • 批准号:
    10630185
  • 财政年份:
    2020
  • 资助金额:
    $ 34.43万
  • 项目类别:
Mechanisms of Impaired Lysosomal Biogenesis and Autophagy in Alcohol-Associated Alzheimer's Disease
酒精相关阿尔茨海默氏病溶酶体生物发生和自噬受损的机制
  • 批准号:
    10405008
  • 财政年份:
    2020
  • 资助金额:
    $ 34.43万
  • 项目类别:
Prevention and treatment of ALD by inducing hepatic mitochondrial uncoupling
诱导肝线粒体解偶联防治ALD
  • 批准号:
    9761397
  • 财政年份:
    2018
  • 资助金额:
    $ 34.43万
  • 项目类别:
Autophagy in Alcoholic Pancreatitis
酒精性胰腺炎中的自噬
  • 批准号:
    9298263
  • 财政年份:
    2017
  • 资助金额:
    $ 34.43万
  • 项目类别:
Autophagy in Alcoholic Pancreatitis
酒精性胰腺炎中的自噬
  • 批准号:
    10189453
  • 财政年份:
    2017
  • 资助金额:
    $ 34.43万
  • 项目类别:
Autophagy in Alcoholic Pancreatitis
酒精性胰腺炎中的自噬
  • 批准号:
    9925046
  • 财政年份:
    2017
  • 资助金额:
    $ 34.43万
  • 项目类别:

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    2023
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Targeting the neurobiology of restricted and repetitive behaviors in children with autism using N-acetylcysteine
使用 N-乙酰半胱氨酸针对自闭症儿童限制性和重复性行为的神经生物学
  • 批准号:
    10619173
  • 财政年份:
    2022
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    $ 34.43万
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High dose acetaminophen with n-acetylcysteine rescue as a novel STAT3 inhibitor with anti-cancer stem cell properties
高剂量对乙酰氨基酚与 n-乙酰半胱氨酸救援作为具有抗癌干细胞特性的新型 STAT3 抑制剂
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N-乙酰半胱氨酸治疗酒精使用障碍的随机对照试验
  • 批准号:
    nhmrc : 2001375
  • 财政年份:
    2021
  • 资助金额:
    $ 34.43万
  • 项目类别:
    Clinical Trials and Cohort Studies Grants
High dose acetaminophen with n-acetylcysteine rescue as a novel STAT3 inhibitor with anti-cancer stem cell properties
高剂量对乙酰氨基酚与 n-乙酰半胱氨酸救援作为具有抗癌干细胞特性的新型 STAT3 抑制剂
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    2021
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    $ 34.43万
  • 项目类别:
Targeting the neurobiology of restricted and repetitive behaviors in children with autism using N-acetylcysteine
使用 N-乙酰半胱氨酸针对自闭症儿童限制性和重复性行为的神经生物学
  • 批准号:
    10221760
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    2020
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    $ 34.43万
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N-acetylcysteineの骨治癒促進効果の検討
N-乙酰半胱氨酸促进骨愈合作用的考察
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  • 财政年份:
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