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Characterization of Torin-1 effects on endothelial colony forming cells (ECFCs) biology

Dietz, L.E.R. (2016) Characterization of Torin-1 effects on endothelial colony forming cells (ECFCs) biology. Research Project 2 (major thesis), Biology.

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Diabetic Retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of blindness in working-aged adults. The hyperglycaemic milieu of diabetes causes functional impairment and loss of endothelial cells resulting in endothelial dysfunction. Endothelial progenitor cells (EPCs) have been recognised as playing a major role in vascular repair of ischaemic tissues as they are able to differentiate into mature endothelium. Endothelial colony forming cells (ECFCs), an EPC subtype, are considered as the bona fide EPCs. ECFCs are able to repair damaged vessels and therefore have a therapeutic potential in the treatment of DR. For clinical use, it is important that ECFCs can be expanded efficiently in vitro without the cells becoming senescent and losing proliferating potential. Although ECFCs can be efficiently expanded in vitro, their replicative potential is limited and the cells ultimately become senescent after long term culture. mTOR inhibitors such as Rapamycin are found to be able to prolong lifespan. Torin-1, an mTORC1/2 inhibitor, was shown to suppress senescence more efficiently than rapamycin and therefore we focussed on Torin-1. Our results provide the first characterisation of the effect of Torin-1 on ECFCs. We established that adding Torin-1 to healthy ECFCs is not beneficial for either proliferation or senescence establishment. However, the drug seems to reduce the numbers of Etoposide-induced senescent ECFCs. Torin-1 is reported to activate autophagy. The complex relations between autophagy, senescence and apoptosis needs to be further elucidated. Furthermore, mTOR inhibition with Torin-1 significantly decreased mitochondrial respiration of ECFCs. Our study warrants further investigation in mTOR inhibitors and senescence and we speculate on the effects of mTOR inhibition on diabetic ECFCs.

Item Type: Thesis (Research Project 2 (major thesis))
Degree programme: Biology
Thesis type: Research Project 2 (major thesis)
Language: English
Date Deposited: 15 Feb 2018 08:26
Last Modified: 15 Feb 2018 08:26

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