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Investigation of the Regulation of Toll-like Receptor Mediated Transcription

Objective

Toll-like receptors (TLRs) are key microbial sensors essential for the development of innate immunity to pathogens[1]. TLR activation induces the expression of inflammatory cytokines, antimicrobial proteins, and regeneration factors. Uncontrolled activation of TLRs leads to the development of fatal inflammatory diseases. TLR activation is tightly controlled to ensure that repeated activation does not lead to sustained activation of target genes - a phenomenon termed TLR-tolerance. Lipopolysaccharide-(LPS)-tolerance applies primarily to inflammatory cytokines but not antimicrobial proteins. Selective inactivation of inflammatory genes, but not antimicrobial genes ensures the host’s ability to continuously build up antimicrobial defences without causing fatal inflammatory responses.
I recently discovered that Bcl-3 mediates LPS-tolerance by inhibiting the activity of NF-kappaB, a major LPS-activated transcription factor. In the absence of Bcl-3, an inhibitory NF-kappaB complex is degraded, the inflammatory response exacerbated and LPS-tolerance abolished. NF-kappaB-binding sites are significantly enriched among tolerisable (inflammatory) genes. I hypothesise that the NF-kappaB binding site of a promoter dictates sensitivity to TLR-tolerance and that Bcl-3-mediated suppression of TLR signaling applies to inflammatory but not antimicrobial genes. The proposed research will test these hypotheses and investigate the underlying molecular mechanisms of Bcl-3-and NF-kappaB-mediated tolerance.

Field of science

  • /medical and health sciences/health sciences/inflammatory diseases
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins

Call for proposal

FP7-PEOPLE-IRG-2008
See other projects for this call

Funding Scheme

MC-IRG - International Re-integration Grants (IRG)

Coordinator

UNIVERSITY COLLEGE CORK - NATIONAL UNIVERSITY OF IRELAND, CORK
Address
Western Road
T12 YN60 Cork
Ireland
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 100 000
Administrative Contact
Mary Cusack (Ms.)