Modulation of Acute Liver Injury

  • Czaja, Mark J. (CoPI)
  • Czaja, Mark J. (PI)

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): The objective of the studies is to define novel molecular pathways that regulate hepatocellular injury and death. Employing models of toxic liver injury our underlying hypothesis has been that cell death is not the passive result of the biochemical effects of the toxin but an active process regulated by cell signaling pathways. Studies have focused on how toxic injury alters hepatocyte responses to tumor necrosis factor-? (TNF) and reactive oxygen species (ROS) which are two central mediators of liver injury. Our investigations have delineated the critical involvement of c-Jun N-terminal kinase (JNK) signaling in hepatocyte death from TNF and ROS and in toxic liver injury, and JNK overactivation has been established as a central mechanism of other forms of hepatic injury. However, the mechanisms by which JNK regulates hepatocyte death after injury remain unclear and are complicated by the fact that JNK isoforms function to alternatively promote or resist cell death depending on the nature of the injury. In contrast to prior investigations that focused on JNK's direct involvement in cell death pathways, our studies have identified stathmin and glutaminase as novel JNK substrates and indicate that JNK2 regulation of cell death is mediated through effects on common cellular functions such as microtubule stabilization, glutamine metabolism and autophagy. Based on these and other preliminary studies, our central hypothesis is that JNK2 signaling regulates hepatocyte injury and death predominantly by altering basic cellular processes including cytoskeletal dynamics and metabolism rather than through direct effects on cell death pathway components. We will test this hypothesis by delineating the mechanisms by which JNK regulates hepatocellular injury and death in studies contained in three Specific Aims. First, we will test the hypothesis that JNK2-dependent phosphorylation of stathmin stabilizes microtubules to block hepatocyte death from ROS and TNF. Second, we will test the hypothesis that JNK2 promotes hepatocellular injury by decreasing levels of the glutamine-metabolizing enzyme glutaminase and ammonia generation, thereby reducing autophagy and leading to cell death. Third, we will test the hypothesis that autophagy protects against liver injury through the mobilization of fatty acids that maintains cellular energy homeostasis and inhibits activation of the mitochondrial death pathway. These studies will delineate novel paradigms by which JNK regulation of common cellular pathways leads to profound effects on the sensitivity of hepatocytes to death after cellular injury. The ultimate goal of these investigations is to better understand how hepatocytes are injured and die in order to prevent this process and the development of hepatic failure in human liver diseases.
StatusFinished
Effective start/end date4/1/926/30/16

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $358,746.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $366,030.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $391,942.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $378,223.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $6,928,847.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $362,370.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $97,984.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $65,324.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $98,996.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $391,942.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $366,030.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $370,797.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $344,438.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $344,438.00

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