Title: Elk1 as a Master Regulator of Fibrogenesis: An Investigation of the Molecular Mechanisms through Which Elk1 May Regulate Lung Fibrosis
Funder: Medical Research Foundation

Abstract: Idiopathic pulmonary fibrosis (IPF) is a severe, progressive respiratory disease for which there are no effective therapies. The survival rates are appalling and worse than most cancers. The pathogenesis of IPF is very poorly understood, however, the current paradigm suggests that recurrent injury to alveolar epithelial cells combined with a failure of those cells to efficiently repair, results in activation of myofibroblasts and uncontrolled deposition of collagen within the lung interstitium. We have recently identified a novel role for the transcription factor Elk1 in regulating expression of the pro-fibrotic integrin αvβ6. We have shown that Elk1 represses the β6 subunit gene basally and limits αvβ6 expression and fibrosis in an in vivo animal model of IPF. Fundamentally, we have shown that IPF patients have significantly lower levels of expression of Elk1 than non-fibrotic controls, which may help explain how the diseases processes start. Together these data have led us to hypothesise that Elk1 acts as a “brake” on fibrogenesis and that loss of Elk1 expression in the lung leads to spontaneous, progressive lung fibrosis. This study aims to further investigate the role of Elk1 in the pathogenesis IPF. We aim to use molecular biology and systems biology approaches to fully characterise the genes and proteins that may be regulated by Elk1 and therefore affected by the loss of Elk1 expression observed in IPF patients. We will utilise primary alveolar epithelial cells and fibroblasts isolated from Elk1 null animals and wild-type controls, and human lung tissue derived from IPF patients and non-fibrotic control donors, to investigate the role of Elk1 as a master regulator of fibrosis in two of the key cells types important for IPF pathogenesis. Following microarray analysis of the genes and proteins regulated by Elk1, we will employ a combination of promoter-luciferase reporter constructs, site-directed mutagenesis and chromatin immunoprecipitation to further investigate the role of Elk1 binding to key genes in the pathogenesis of IPF. Finally, we will utilise Elk1 null animals to determine if loss of Elk1 in vivo is sufficient for spontaneous, age-related development of lung fibrosis, or whether loss of Elk1 results in progressive fibrosis in a bleomycin-model of pulmonary fibrosis. Current in vivo models of IPF of limited due to the fact that the fibrosis that occurs is not progressive and resolves spontaneously with time. Our data suggests that this may be due to on-going Elk1 expression which limits the fibrotic response. Investigating age-related and long-term bleomycin treatment fibrotic responses in Elk1 null animals and wild-type controls will enable us to determine whether Elk1 null animals would represent a new, improved, and more clinically relevant in vivo model of pulmonary fibrosis. Together, the studies described in this proposal will shed important light on the role of Elk1 as a master regulator of multiple pathways in IPF and further elucidate the mechanisms driving the development and progression of IPF.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: RESPIRATORY