Acetaminophen (APAP) toxicity is the leading cause of acute liver failure. The mouse model of APAP hepatotoxicity is highly reproducible and widely utilized to elucidate the mechanisms of liver injury, due to drugs and toxins. Recently, a major role for signal transduction pathways in modulating toxicity downstream of APAP metabolism has been identified using this model. The activation of c-jun-N-terminal kinase (JNK) and its effects on mitochondria have been found to be critical in the signaling pathway leading to APAP-induced necrosis. The goal of this proposal is to elucidate the mechanism of APAP-induced activation of MAPK kinases and the significance, targets, and consequences of the targeting of activated JNK to mitochondria in carrying out the lethal effects of APAP in hepatocytes.
The aims are as follows: (1) Determine the role and significance of binding of P-JNK to specific mitochondrial target protein which has been identified in the pathogenesis of APAP hepatotoxicity: Binding partners will be identified by immunoprecipitation and proteomic approaches and the importance of the mitochondrial JNK target will be determined by adenovirus-shRNA knockdown;the effects of pure activated JNK on mitochondrial function and integrity will be assessed: (2) Determine the signal transduction pathways that lead to both early and sustained activation of JNK in APAP toxicity: the interplay of various upstream pathways such as GSK32, Ras/Raf-1, MLK-3, MEKK-1, PKC1, Akt 1+2, will be examined using antisense oligonucleotide silencing and/or knockout mice to elucidate the initial ASK-1 independent activation of JNK required for subsequent ASK-1 dependent sustained JNK activation;(3) Determine the role of ER stress in APAP toxicity: the plausible contribution of ER stress to the signal transduction pathways leading to mitochondrial collapse will be assessed by exploiting knockout or over expression of the key ER stress sensor, GRP78;(4) Determine the role of RIP kinases in APAP-induced necrosis and the relationship to the GSK/JNK/Sab pathway: RIP may play a key role in signal transduction pathways leading to APAP necrosis which will be assessed using specific inhibitors and antisense silencing of RIP-1. The elucidation of these four aims will lead to an improved understanding of the role and interplay of signal transduction pathways and mitochondria in hepatotoxicity and which will identify new therapeutic targets.
Adverse effects of drugs such as acetaminophen on the liver, which is the leading cause of acute liver failure in the United States, are a major stumbling block in drug development. This proposal is aimed at developing a detailed understanding of the molecular pathways in the liver that lead to injury (killing of liver cells) and identifying new therapeutic targets to prevent injury form acetaminophen or other causes.
|Win, Sanda; Than, Tin Aung; Zhang, Jun et al. (2018) New insights into the role and mechanism of c-Jun-N-terminal kinase signaling in the pathobiology of liver diseases. Hepatology 67:2013-2024|
|Huo, Yazhen; Win, Sanda; Than, Tin Aung et al. (2017) Antcin H Protects Against Acute Liver Injury Through Disruption of the Interaction of c-Jun-N-Terminal Kinase with Mitochondria. Antioxid Redox Signal 26:207-220|
|Apte, Udayan; Kaplowitz, Neil (2017) Heparan sulfate promotes recovery from acute liver injury: Inhibition of progressive cell death or enhanced regeneration? Hepatology 66:1381-1383|
|Iorga, Andrea; Dara, Lily; Kaplowitz, Neil (2017) Drug-Induced Liver Injury: Cascade of Events Leading to Cell Death, Apoptosis or Necrosis. Int J Mol Sci 18:|
|Pyzik, Michal; Rath, Timo; Kuo, Timothy T et al. (2017) Hepatic FcRn regulates albumin homeostasis and susceptibility to liver injury. Proc Natl Acad Sci U S A 114:E2862-E2871|
|Zhang, Jun; Min, Robert W M; Le, Khanh et al. (2017) The role of MAP2 kinases and p38 kinase in acute murine liver injury models. Cell Death Dis 8:e2903|
|Huo, Yazhen; Yin, Shutao; Yan, Mingzhu et al. (2017) Protective role of p53 in acetaminophen hepatotoxicity. Free Radic Biol Med 106:111-117|
|Suda, Jo; Dara, Lily; Yang, Luoluo et al. (2016) Knockdown of RIPK1 Markedly Exacerbates Murine Immune-Mediated Liver Injury through Massive Apoptosis of Hepatocytes, Independent of Necroptosis and Inhibition of NF-?B. J Immunol 197:3120-3129|
|Dara, Lily; Liu, Zhang-Xu; Kaplowitz, Neil (2016) Questions and controversies: the role of necroptosis in liver disease. Cell Death Discov 2:16089|
|Smith, Andrew K; Petersen, Brenden K; Ropella, Glen E P et al. (2016) Competing Mechanistic Hypotheses of Acetaminophen-Induced Hepatotoxicity Challenged by Virtual Experiments. PLoS Comput Biol 12:e1005253|
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