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Title: Modulation of the anti-angiogenic protein FKBPL : implications for a host of diseases, including cancer
Author: Bennett, Rachel
ISNI:       0000 0004 5917 5796
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2015
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FKBPL is a secreted anti-angiogenic protein, with a therapeutic peptide, ALM201, based on the active domain of FKBPL shortly entering phase I clinical trials. The aim of this thesis was to characterise the effects of FKBPL modulation on physiological and pathological angiogenesis, to identify FKBPL-associated pathways and to determine how FKBPL transcription, translation and secretion is mediated. To study the effects of FKBPL modulation on angiogenesis and tumour growth, a novel amphipathic peptide, RALA, was used to deliver FKBPL siRNA and FKBPL cDNA in vitro and in vivo, to ZR-75-1 xenografts; increased FKBPL was I associated with delayed tumour growth, prolonged survival and decreased microvessel density (MVD), whilst decreased I expression resulted in increased MVD and stemness. The physiological impact of endogenous FKBPL was established by development of a Fkbpl+/- mouse; Fkbpl-/- mice I were embryonically lethal prior to E8.5, suggesting a critical role for FKBPL in embryonic development. However, whilst Fkbpl+/- embryos showed some vascular irregularities, the mice developed normally. In murine angiogenesis models including the aortic ring, sponge, and tumour growth assays, Fkbpl+/- mice exhibited significantly increased sprouting, enhanced vessel recruitment and faster tumour growth, respectively, compared to their wild -type littermates, supporting the anti-angiogenic function of FKBPL. Furthermore, Fkbpl+/ mice were more prone to obesity and were less able to regulate glucose levels; interestingly, ALM201 was able to normalise this phenotype. SIRT1, a key gene involved in ; obesity and diabetes was positively regulated by FKBPL, both in vitro and in vivo, going some way to explaining these effects. Furthermore, manipulation of the SIRT pathway also potentiated the anti-tumour activity of FKBPL. The regulation of FKBPL by pro-angiogenic stimuli, and its secretory pathway was,also investigated. FKBPL was secreted via the Golgi body to a greater extent in human microvascular endothelial cells compared to tumour cells, in keeping with its anti-angiogenic role. Protein and mRNA expression was unaffected by hypoxia and other angiogenic cytokines, VEGF, bFGF or IL8; whilst hypoxia inhibited its secretion in a normal endothelial cell line, but not in a cancer cell line. In conclusion, this indicates that FKBPL is a potent secreted anti-angiogenic protein, and is essential for normal 1 physiological development. As well as being an anti-angiogenic drug with potential for use in cancer treatment, ALM201 also has the potential to reduce weight gain and to normalise blood glucose in patients deficient in FKBPL, opening up further opportunities for future study.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available