Award details

Regulation of Toll/L-1 mediated responses through a novel receptor IL-1RIII

Reference	BB/C515798/1
Principal Investigator / Supervisor	Professor Eva Qwarnstrom
Co-Investigators / Co-Supervisors	Professor William Holcombe
Institution	University of Sheffield
Department	Genomic Medicine
Funding type	Research
Value (£)	203,962
Status	Completed
Type	Research Grant
Start date	11/07/2005
End date	10/11/2008
Duration	40 months

Abstract

This project focuses on characterisation of a novel receptor, the type III IL-1 receptor IL-1RIII) that regulates cellular functions induced through members of the Toll/Interleukin-1 receptor family (TIR). Activation of the system is initiated through the common TIR domain, recognised in vertebrates, insects and plants which constitutes an evolutionary conserved set of regulatory sites controlling innate immunity and inflammation. Dis-regulation of this pathway constitutes the basis for breakdown of fundamental responses, such as controlled host-defence mechanisms, in a large variety of species. Sequence analysis and data base searching confirmed that the novel receptor, IL-1RIII, is a glycosylated cell surface protein and demonstrated it to constitute a unique gene product, present in a variety of species. Our data show that association of IL-1RII with the type I IL-1 receptor affects receptor function and significantly potentiates TIR signalling and gene regulation. Recent experiments using siRNA confirmed the significance of this protein in regulation of immune and inflammatory responses. Thus, blocking synthesis of the IL-1RIII results in a 50 per cent reduction in cytokine receptor binding and in inhibition of TIR induction of NF-kB, the major regulatory transcription factor of immune and inflammatory responses. The experiments outlined in this proposal are designed to characterise the mechanisms involved in activation of the novel IL-1 receptor and to determine the consequences of its involvement in control of inflammatory and immune responses. Initially, we will determine the specific sites within the TIR domain and the TIR complex components involved in regulation through IL-1RIII (AIM1). In addition, we will assess the downstream kinases involved in NF-kB and MAP kinase activation induced through IL-1RIII regulation of inflammatory responses (AIM II). Subsequently, we will assess the effects of IL-1RIII on activation levels and kinetics of gene regulatory steps in both pathways using confocal microscopy and GFP-based methods and monitor signalling events in single live cells and in real time (AIM III). Ultimately the data from AIMs II and III will constitute the basis for mathematical analysis and computational modelling of regulation of the NF-kB and MAP kinase signalling networks through IL-1RIII (AIM IV). The results will outline the role of a novel cytokine receptor and thereby improve our knowledge of regulation of fundamental cellular responses related to evolutionarily conserved host defence mechanisms.

Summary

unavailable

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	Immunology, Structural Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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