Liver fibrosis caused by hepatitis viruses and drugs has become a serious problem since it affects tens of millions of people worldwide. Liver cirrhosis, the end-stage irreversible consequence of fibrosis, is now the seventh leading cause of death in the United States and has no available therapies except transplantation. Regeneration of the liver after injury requires both a well-orchestrated proliferation of hepatocytes as well as extracellular matrix (ECM) remodeling to restore hepatic architecture and functions. Liver fibrosis results from the excessive secretion of ECMs in response to chronic liver damage. However, how deposited ECM contributes to the critical turning point from normal to abnormal healing is unknown. The overall long-term objective of this research is to increase our understanding of the molecular mechanisms underlying proper three-dimensional reconstitution of ECM architecture induced by initial fibronectin (Fn) deposition. The deposition of Fn has an important role to form """"""""provisional matrix"""""""" during the early phase of tissue remodeling, followed by replacement of Fn by collagen fibrils. To explore the role of Fn in adult tissue, we have recently generated transgenic mice that enable us to analyze tissue remodeling of the liver without any Fn. Production of ECM, including Fn, is enhanced by transforming growth factor beta (TGF-beta) in many fibrotic disorders. However, the mechanisms by which TGF-beta is activated during liver injury are still unknown. The central hypothesis of the proposed research is that Fn and locally activated TGF-beta have crucial roles in fibrillogenesis of collagens produced by activated hepatic stellate cells in response to liver injury. We will analyze how deposition of Fn and activation of TGF-beta are controlled during liver injury and how Fn- and TGF-beta-mediated fibrillogenesis is regulated utilizing Fn and beta6 integrin mutant mice as in vivo model systems. Our three Specific Aims are the following:
Aim 1 is to determine how the absence of Fn affects initial healing after liver injury;
Aim 2 is to determine whether the lack of Fn attenuates liver fibrosis during chronic liver injury;
and Aim 3 is to determine how alphaVbetaG integrin-mediated TGF-beta activation regulates ECM production of activated hepatic stellate cells throughout the process of liver injury. This study will provide novel insights into molecular mechanisms underlying abnormal tissue remodeling and also will have profound clinical impact by suggesting new therapeutic strategies for fibrotic disorders.
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