Investigating The Role Of Beta1 Integrin In Hepatic Stellate Cell Activation And Liver Fibrosis

Abstract

The University of ManchesterKatherine MartinDegree: Doctor of Philosophy (PhD)Thesis Title: Investigating the Role of Beta1 Integrin in Hepatic Stellate Cell Activation and Liver FibrosisDate: 20th March 2015Liver fibrosis is characterised by progressive deposition of type 1 collagen-rich extracellular matrix in response to iterative liver injury. The progressive accumulation of scar tissue within the liver predisposes to the development of hepatocellular carcinoma, and ultimately leads to organ failure. Liver fibrosis is an increasing cause of morbidity and mortality. However, current treatment options are limited, and the only curative option for end stage liver disease is transplantation. Anti-fibrotic agents are urgently needed to halt, or reverse, the fibrotic process; however, to date, they have remained frustratingly elusive.The primary cell type responsible for laying down the pathological fibrotic matrix is the hepatic stellate cell (HSCs). In the healthy liver, HSCs are quiescent vitamin A storing cells, however, in response to liver injury they are activated into proliferative, migratory and contractile myofibroblasts. A number of cytokines and transcription factors are implicated in this activation process; in addition, biomechanical forces have emerged as an important regulator. The integrins are a family of cell surface receptors, which are predominately involved in mediating cellular interactions with the microenvironment. The work presented in this thesis demonstrates that beta1 integrin (Itgb1) plays an important role in HSC activation through regulation of the actin myosin cytoskeleton, and thereby, the cell's ability to sense and respond to changes in the biomechanical microenvironment. By identifying and investigating downstream effectors of Itgb1 in HSC activation, the group I p21-activated kinases (Paks) were discovered as potential therapeutic targets in liver fibrosis. In addition, alpha11 integrin was identified as a fibroblast-specific partner of Itgb1 in HSCs, which crucially, may allow HSC-specific targeting of Itgb1. Taken together, the data presented in this thesis suggest that disrupting Itgb1 signalling in HSC activation may be a novel therapeutic avenue for liver fibrosis. In particular, pharmacological inhibition of the downstream effectors, the group I Paks, has shown promise as an anti-fibrotic both in vitro and in vivo.  

Date of Award	31 Dec 2015
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Karen Piper Hanley (Supervisor) & Neil Hanley (Supervisor)