Young, Pamela A. (2013) The effect of Retinol Binding Protein on the Proteome of muscle cells. PhD thesis, National University of Ireland Maynooth.

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Abstract

Vitamin A is essential for normal embryonic development and vision. Retinol binding protein (RBP) and its receptor, STRA6, are vital for the maintenance of intracellular stores of vitamin A. Recently, elevated serum RBP concentration has been implicated as a contributing factor to the development of insulin resistance and type II diabetes. However, conflicting opinions exist as to how increased RBP levels can cause insulin resistance. Some suggest it is as a result of the activation of macrophages in adipose tissue and the secretion of cytokines. Others suggest it is as a result of RBP induced STRA6 phosphorylation, and the activation of the JAK/STAT signalling pathway. Regardless of the mechanism, reducing circulating levels of RBP may be a novel strategy for the treatment of type II diabetes. Several small molecules have been designed to promote renal clearance of RBP, thus lowering serum levels. In order to consolidate the theories surrounding RBP induced insulin resistance, a proteomic study was devised to determine the direct effect of RBP on muscle cells, since the muscle is the main target of insulin induced glucose uptake. Results suggest that RBP may be affecting the enzymes involved in glucose storage and glycogen catabolism. Artificial methods aimed at reducing serum RBP levels may act by preventing RBP induced glycogen disruption. In a related study, it was noted that small molecules aimed at reducing circulating RBP levels had a direct effect on muscle cells to stimulate glucose uptake. This phenomenon occurred independently of the predicted mechanism of action. A second proteomic study was conducted to determine the direct mechanism of action of the compounds in muscle cells. The molecules appear to stimulate the influx of glucose by reducing the ATP yield from oxidative phosphorylation and enhancing the utilisation of alternate energy stores. The C-terminal region of STRA6 appears to be a large SH2 motif-containing intracellular segment which may be capable of forming an independently folding domain. As such it may represent the site of interaction with other proteins in the system. Therefore, it was cloned, expressed and characterised. The secondary structure of the domain was shown to be largely α-helical and a model was constructed. Possible functional roles for this region were investigated.

Item Type:	Thesis (PhD)
Keywords:	Retinol Binding Protein; Proteome; muscle cells;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	4880
Depositing User:	IR eTheses
Date Deposited:	09 Apr 2014 10:53
URI:
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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