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Title: Differential expression of connective tissue growth factor (CTGF) in fibrogenesis : regulation by simvastatin
Author: Watts, Keira Louise.
Awarding Body: Keele University
Current Institution: Keele University
Date of Award: 2004
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Connective Tissue Growth Factor (CTGF) is a potent, pro fibrotic mediator, which acts downstream of and in concert with Transforming Growth Factor (TGF)p, to drive fibrogenesis. Significant upregulation of CTGF has been reported in fibrogenic diseases including idiopathic pulmonary fibrosis (IPF). IPF typically features excessive fibroblast proliferation and extracellular matrix (ECM) deposition, features that may be partially due to CTGF over-expression. In this thesis, basal expression of CTGF in response to TGFp (Sng/ml) is confirmed in primary lung fibroblasts (lMR90 and HIPF). Gene expression is studied using competitive RT-PCR; western blotting and immunofluorescence used to measure protein levels. In contrast to IMR90 cells, TGFp significantly induces CTGF (gene and protein) in a timedependent fashion in HIPF cells. The thesis also provides novel insight into elevated CTGF induction and response to TGFp in Rheumatoid Arthritis-derived synovial fibroblasts compared to Osteoarthritis fibroblasts, suggesting that the role of CTGF is not selective to the lung and is implicated in arthropathies. There is currently no effective therapy for aborting fibrogenesis. Simvastatin has been shown to have anti fibrotic potential in renal fibroblasts; however similar action with the context of lung fibrosis has not been documented. Simvastatin is shown to reduce basal gene and protein expression of CTGF in lung fibroblasts and overrides TGFp-induction in a concentration-dependent manner. This modulation of CTGF, which occurs through inhibition of the cholesterol synthesis pathway, is associated with changes in aSMA and collagen gel contraction.Signalling pathways underlying Simvastatin effect on CTGF-TGFB interaction are evaluated using transient reporter transfections of a plasmid construct containing the CTGF promoter linked to luciferase. Simvastatin inhibits CTGF promoter activity in a concentration-dependent fashion inducing an 8.52 fold down regulation over TGFB stimulated at 10)lM concentration. Separate studies explore the role of the small GTPases namely Rho and Ras and show that geranylgeranylpyrophosphate (GGPP), but not farnesylpyrophosphate (FPP) induces CTGF promoter activity following Simvastatin inhibition. In conclusion, this novel data confirms Simvastatin's ability to modulate CTGF expression, and thus fibrogenesis, implicating a critical role for small GTPases, specifically Rho, in CTGF signalling.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available