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Title: Dysfunctional response to transforming growth factor-beta contribute to the development of familial pulmonary arterial hypertension due to mutations in bone morphogenetic protein type II receptor
Author: Davies, R. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2010
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TGF-β1 significantly inhibited the growth of human and mouse control cells. Cells harbouring dysfunctional BMPR-11 signalling were resistant to this growth inhibition. Mutant BMPR-11 cells had reduced BMP4 induced Smad 1/5 phosphorylation, reduced transcription of the BRE-luciferase reporter as well as reduced induction of inhibitors of DNA binding gene (Id1, 2 and 4) transcription. However, there was no difference in the level of activation of the TGF-β pathway, either at second messenger or transcriptional level, between control and mutant PASMCs to account for the loss of the growth inhibitory effects of TGF-β in the mutant cells. Microarray data generated from our PASMCs indicated a potential increase in the NFκB signalling pathway in BMPR-11 mutant PASMCs. Immunoblotting revealed increased basal expression of the NFκB signalling subunit, phospho-p65, in mutant cells indicating increased baseline activity of this signalling pathway. ELISA showed increased baseline IL-8 release in the mutant PASMCs compared with controls. Furthermore, incubation of BMPR-11 mutant PASMCs with an IL-8 neutralising antibody re-sensitised the mutant cells to the inhibitory growth effects of TGF-β returning them to the phenotype of control PASMCs. BMPR-11 signalling was also found to be crucial I the control of growth of HPAECs. BMP9 was shown to phosphorylate both Smad 1/5 and Smad 2 via ALK1 in conjunction with ActR-11 and BMPR-11. A reduction in BMPR-11 expression reduced the growth inhibitory effects of BMP9. Inhibition of NFκB signalling, thus normalising TGF-β responses in the setting of FPAH, may be a promising therapeutic target.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available