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Lilani Abeywickrama; The Role of the MRTFA-SRF pathway in fibroblast to adipocyte transdifferentiation in Thyroid Eye Disease. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4097.
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Thyroid eye disease (TED) is a progressive autoimmune disease in which orbital fibroblasts transdifferentiate into adipocytes and extraocular muscles undergo fibrosis. Myocardin-related transcription factor A (MRTFA) is a co-factor of the transcription factor Serum Response Factor (SRF). MRTFA binds to cytoplasmic G-actin and translocates to the nucleus, upon stimulation of actin polymerization. The actin-MRTF-SRF circuit regulates the expression of target genes responsible for regulation of the actin cytoskeleton. The downregulation of MRTFA causes a decrease in SRF activation, which facilitates the conversion of fibroblasts to adipocytes. We hypothesize the two phenotypes, seen in TED, are associated with the SRF-MRTFA pathway. Our study focuses on how diseased cells differ from control cells in terms of their MRTFA content and how this relates to their propensity to differentiate into adipocytes.
This project was divided into 3 sections: 1) Oil Red O staining to examine for the presence of adipocytes in TED cells; 2) Immunostaining for MRTFA and IGFR1 in diseased cells; and finally 3) Western Blot Analysis to determine whether levels of specific proteins (MRTFA, IGFR-1) are present in samples of affected cells.
Our results demonstrated that fibroblasts underwent adipocyte differentiation in vitro. We found a significantly high nuclear-cytoplasmic ratio in diseased cells that implied greater baseline activity of SRF-MRTFA in affected OF and our final experiment identified similar quantities of protein MRTFA in both control and TED cells.
In conclusion, SRF-MRTFA is linked with the process of adipogenesis and a dual pathway is involved in the pathology of TED.
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