Role of Hypoxia Inducible Factors in Liver Fibrosis (360G-Wellcome-207279_Z_17_Z)

Hepatic fibrosis is a chronic liver disease associated with the accumulation of scar tissue caused by the excessive deposition of extracellular matrix (ECM) proteins. The Activation of hepatic stellate cells (HSCs) is the initiating event in liver fibrosis, and as such uncovering the molecular determinants behind this activation is of great importance in understanding the disease. The expression of UCHL1, a deubiquitinase enzyme, is dramatically elevated upon hepatic stellate cell (HSC) activation and is involved in the regulation of HSC proliferation, however the precise targets of UCHL1 in this context is unclear. UCLH1 has recently been identified as a HIF1 alpha deubiquitinase which causes increased HIF1 activity under normoxic and hypoxic conditions by disrupting the degradation of HIF1 alpha. Preliminary data has suggested that HIF1a levels are elevated in activated HSCs and this activation is dependent on UCHL1. This project aims to build on these findings with the following aims - 1. Examine relationship between UCHL1 and HIF1 exploring the contribution to the fibrotic phenotype. 2. Examine effects of elevated UCHL1 and HIF1 on cellular proliferation. 3. Analyse markers of fibrosis and HIF activity.