The role of the alphavbeta8 integrin in hepatic inflammation and fibrosis. (360G-Wellcome-085187_Z_08_Z)

TGF-beta is a major pro-fibrogenic cytokine and therefore mechanisms that regulate TGFbeta signaling within the liver are likely to play a critical role in liver fibrogenesis. Integrins represent a major mode of communication between the matrix, inflammatory cells, fibroblasts and epithelia. The alphavbeta8 integrin has the potential to bind the RGD sequence in the latency associated peptide (LAP) of TGF-beta1 and -beta3 and activate latent TGF-beta. We hypothesise that the integrin alphavbeta8 is a major regulator of TGF-beta activation during hepatic fibrogenesis, and that inhibition of alphavbeta8-mediated TGF-beta activation will result in reduced activation of latent TGF-beta, decreased myofibroblast activation and liver fibrosis. Aims: 1) To determine which cell types express alphavbeta8 in normal and injured liver. 2) Using genetic approaches (inducible and tissue specific deletion of alphavbeta8) in liver fibrosis models to dissect which cell types are important regulators of h epatic alphavbeta8-mediated TGFbeta activation. 3) Measurement of alphavbeta8-mediated TGFbeta activation by HSC, and analysis of HSC phenotype following manipulation of alphavbeta8 expression. 4) To determine how alphavbeta8-mediated TGFbeta activation is regulated in hepatic stellate cells. These studies should facilitate the development of new anti-fibrotic therapies by clarifying the mechanisms that regulate TGFbeta activation in hepatic fibrogenesis.