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Title: Molecular determinants of phenotype of orbital fibroblasts in thyroid eye disease
Author: Yang, I-Hui
ISNI:       0000 0004 8500 4640
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Thyroid eye disease (TED) is an autoimmune disease originating from the thyroid gland and affecting orbital contents. The orbital fibroblasts are a key component in the pathogenesis of TED, which includes immune reaction/inflammation, adipogenesis, hyaluronic acid (HA) secretion, and fibrosis. Previous work in our lab has shown that TED adipogenic and fibrotic phenotypes could be modelled in a 3D environment in vitro. Spontaneous lipid droplet (LD) formation was observed exclusively in 3D soft matrix, more prominent in TED orbital fibroblasts, and enhanced under pressure load simulating elevated intraorbital pressure, suggesting the involvement of mechanical factors in TED pathogenesis. We used this 3D model to further investigate three aspects of the TED phenotype, which includes LD formation, HA secretion, and fibrosis (cell contractility). We found that myocardin-related transcription factor (MRTF), an important transcriptional cofactor for mechanotransduction, regulated the fibrotic phenotype rather than LD formation in orbital fibroblasts. Spontaneous LD accumulation in orbital fibroblasts was found to involve fatty acid uptake, but none of the classical chemical adipogenesis associated components. Rather, we found that it was linked to the expression of perilipin 2 (PLIN2), a protein surrounding LDs. The presence of stimulated macrophages significantly increased HA production and contractility in orbital fibroblasts, but did not promote LD accumulation. This work suggested that the overall TED phenotype may be regulated by inflammation: LD accumulation mediated by cytokine via upregulating the level of PLIN2, HA secretion induced by macrophages, and fibrosis (cell contractility) stimulated by macrophage through changes in actin dynamics and downstream MRTF/serum response factor (SRF) signalling.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available