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Title: Identifying components of the TGF B-1 pathway in renal fibrosis
Author: Shuttleworth, Victoria Gemma
ISNI:       0000 0004 8505 7419
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 2019
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Chronic Kidney Disease (CKD) is characterised by the expression of alpha smooth muscle actin (α-SMA) and Collagen from the aberrant infiltration and proliferation of myofibroblasts. This results in renal fibrosis and ultimately end stage renal disease (ESRD). CKD is a growing health problem resulting in significant costs to the NHS, making the identification of novel therapeutic targets for the treatment of CKD a key clinical priority. Transforming growth factor β-1 (TGF -1) plays a critical role in the persistent activation of myofibroblasts leading to fibrosis. TGF -1 signals through transmembrane serine-threonine kinase type I and II receptors to phosphorylate SMAD3, a downstream intracellular receptorregulated SMAD protein (R-SMAD). Upon phosphorylation, activated SMAD3 translocates to the nucleus to regulate the transcription of fibrotic genes such as α-SMA and Collagen. Studies have shown SMAD3 to have an important role in fibrosis. This work sought to identify novel components of TGF β-1 signalling in order to increase our understanding of the pathway and identify potential therapeutic targets to treat CKD. This was achieved through siRNA and compound screening in renal cells. Here, three novel components of the TGF β-1 pathway are described. SET9, a lysine methyltransferase and Aurora Kinase A, a serine/threonine kinase were shown to interact with SMAD3 to upregulate its transcriptional activity. Inhibitors of SET9 and Aurora Kinase A were shown to have anti-fibrotic activities by reducing TGF β-1 signalling. Additionally, SETDB1, a different lysine methyltransferase was also shown to interact with SMAD3, acting as a brake on TGF β-1 signalling. Identification of novel components of TGF β-1 signalling in renal fibrosis will aid our understanding of the mechanisms of fibrosis to develop novel therapeutics for the treatment of CKD.
Supervisor: Not available Sponsor: Glaxo Smith Kline (GSK) ; Northern Counties Kidney Research Fund (NCKRF)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available