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Regulation of Inflammatory and Anti-Apoptotic Signals through TILRR, a Novel IL-1RI Co-Receptor The Impact of TILRR Single Nucleotide Polymorphisms

Nichols, Andy (2017) Regulation of Inflammatory and Anti-Apoptotic Signals through TILRR, a Novel IL-1RI Co-Receptor The Impact of TILRR Single Nucleotide Polymorphisms. PhD thesis, University of Sheffield.

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Members of the Interleukin-1 (IL-1) and Toll-like receptor families are critical components of the human innate immune system. They mediate inflammatory responses following detection of pathogens and damage. These same pathways of host defence have however been implicated in the pathogenesis of a number of diseases including atherosclerosis and cancer. Activation of the receptor systems is induced by ligand binding and controlled by association of co-receptors. Toll-like and IL-1 receptor regulator (TILRR) is a cell surface heparan sulfate proteoglycan which has been demonstrated to interact with the IL-1 receptor (IL-1RI) and potentiate pro inflammatory and anti-apoptotic responses. In the present study polymorphisms within the TILRR protein were located using the 1000 genome project database. In silico methods were applied to select a subset of candidate functional single nucleotide polymorphisms (SNPs) within predicted sites of interaction. Subsequent in vitro studies identified two TILRR polymorphisms, which selectively regulate canonical and non-canonical control of NF-κB signalling downstream of IL-1RI activation. One of these SNPs also impacts on signalling downstream of TLR4 activation. This study concludes with the initial steps of generating a zebrafish model of TILRR screening, which shows that changes in adapter protein levels, such as induced by TILRR, control NF-κB activation and inflammatory cell recruitment in vivo. Future investigations of the function of TILRR and impact of TILRR SNPs will expand on results from this studies to identify conditions where such mutants may be particularly relevant, and continue development of the zebrafish model to include a range of aspects of TILRR function. The results show pronounced effects of TILRR-induced amplification on inflammatory and anti-apoptotic signals, and demonstrate that single nucleotide polymorphisms within the TILRR protein impart selective control of NF-κB induced responses. Future studies will examine the relevance of the distinct regulation in disease and the potential of the identified functional SNPs as therapeutic targets.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Depositing User: Mr Andy Nichols
Date Deposited: 26 Mar 2018 14:36
Last Modified: 26 Mar 2018 14:36
URI: http://etheses.whiterose.ac.uk/id/eprint/19707

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