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Title: Characterisation of the role of long non-coding RNAs in lung fibroblasts from control and idiopathic pulmonary fibrosis patients
Author: Hadjicharalambous, Marina
ISNI:       0000 0004 7660 0280
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 2018
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Idiopathic pulmonary fibrosis (IPF) is a fatal progressive chronic disease characterised by excessing scarring of the lungs leading to irreversible decline in lung function. The aetiology and pathogenesis of the disease are still unclear, although lung fibroblast activation and secretion of fibrotic and inflammatory mediators have been strongly associated with the development and progression of IPF. Significantly, long non-coding RNAs (lncRNAs) are emerging as novel modulators of multiple biological processes although their function and mechanism of action is poorly understood and their role in IPF is uncharacterised. To better understand the underlying pathological features of IPF, the phenotypic changes of control and IPF lung fibroblasts as well as the role of lncRNAs in IPF and during TGF-ß1, PDGF-AB and IL-1ß-induced activation of lung fibroblasts were examined. Overall, IPF fibroblasts demonstrated an increased fibrotic and a reduced inflammatory and proliferative profile compared to controls. The phenotypic differences of control and IPF fibroblasts were also reflected at the epigenetic level. Using chromatin immunoprecipitation combined with sequencing (ChIP-seq), the distribution profile of the histone modification H3K4me1 was shown to be notably different between the two fibroblast populations. RNA-sequencing (RNA-seq) and microarray technology identified several differentially expressed lncRNAs in lung fibroblasts upon TGF-ß1 and IL-1ß activation. Subsequent knockdown studies focused on the functional roles of four lncRNAs namely LINC00960, LINC01140, IL7AS and MIR3142HG. LINC01140 was found to be a negative regulator of the inflammatory response, while both LINC00960 and LINC01140 were shown to be positive regulators of proliferation. Additionally, IL7AS and MIR3142HG were also shown to regulate the inflammatory response in control and IPF fibroblasts. Collectively, the results of this thesis propose that lncRNAs may be important regulators of lung fibroblast functions and consequently mediate the progression of IPF.
Supervisor: Lindsay, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available