Project Details
Description
PROJECT SUMMARY/ABSTRACT
Hepatocyte injury and cell death underlie the development of hepatic failure and progression to the complications
of cirrhosis and hepatocellular carcinoma in human liver disease. Despite recent advances, the mechanisms of
hepatocyte injury and death remain poorly understood. Liver injury results largely from the effects of factors
generated by the excessive sterile inflammatory response that accompanies hepatocyte injury and death. Over
the previous funding period we demonstrated that conditions that predispose to liver injury are associated with
decreased function of the degradative pathway of autophagy in both hepatocytes and macrophages. We and
others have also shown that autophagy functions to prevent liver injury and decrease hepatic inflammation, but
the mechanisms of autophagy’s protective effects remain unclear. The objective of this proposal is to delineate
novel mechanisms by which impaired autophagy in hepatocytes and macrophages promotes liver injury and
inflammation. Preliminary studies indicate that macrophages and hepatocytes with decreased autophagy have
an increased proinflammatory response to toll-like receptor 2 (TLR2) stimulation that causes liver injury. In
addition, hepatocytes with impaired autophagy become sensitized to cytokine toxicity from the synergistic effects
of IL-1β and TNF, and once injured actively secrete proinflammatory damage-associated molecular patterns
(DAMPs) in exosomes. Based on these and other preliminary findings, the central hypothesis of this proposal
is that during liver injury the effects of decreased hepatic autophagy on cell signaling pathways both amplify the
proinflammatory activation of macrophages and hepatocytes by increasing the TLR2-mediated sterile
inflammatory response, and sensitize hepatocytes to IL-1β-dependent cell death which further sustains
inflammation. We will test this hypothesis through investigations contained in three Specific Aims that will
examine liver injury in cell culture and mouse models with a genetic decrease in autophagy. First, we will test
the hypothesis that impaired autophagy promotes liver injury by hyperactivation of a TLR2-dependent innate
immune response in both macrophages and hepatocytes through the mechanism of decreased docking protein
1 degradation which results in reduced extracellular signal-regulated kinase 1/2 signaling. Second, we will test
the hypothesis that with decreased autophagy the energy demands of the proinflammatory cytokines IL-1β and
TNF induce ATP depletion, lysosome permeabilization and cathepsin L-dependent hepatocyte necrosis. Third,
we will test the hypothesis that with decreased autophagy injured hepatocytes induce a local and systemic innate
immune response through the active secretion of exosomes containing DAMPs that are normally sequestered
and degraded by autophagy. The ultimate goal of the investigations is to understand how impaired autophagy
promotes liver disease through altered innate immunity and hepatocyte death signaling in order to develop new
treatment modalities for human liver disease.
Status | Active |
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Effective start/end date | 4/1/92 → 7/31/24 |
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: $58,625.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $6,928,847.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $97,984.00
- 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: $292,575.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $344,438.00
- 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: $362,890.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $378,223.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $362,370.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $65,324.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $344,438.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $344,438.00
- National Institute of Diabetes and Digestive and Kidney Diseases: $289,183.00
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