Molecular mechanisms controlling peptide selection for immune recognition. (360G-Wellcome-104647_Z_14_Z)
I have discovered that TAPBPR is a novel MHC class I specific component in the antigen processing and presentation pathway. This work represents a major advance in the field of MHC biology. It is now essential to investigate the specific function of TAPBPR in the immune system in order to understand its role in health and disease. My key research goals are to: 1)Determine the role of TAPBPR in MHC I peptide selection. Techniques used will include sequencing the peptide repertoire presented to the immune system by mass spectrometry in wild-type and TAPBPR depleted cells, in vitro peptide exchange assays for TAPBPR function on MHC molecules, and T cell assays to assess the consequence of TAPBPR depletion on recognition of MHC by T lymphocytes. 2)Characterise the molecular mechanisms underpinning TAPBPR function. Experimental methods used will include affinity chromatography with mass spectrometry to identify other TAPBPR binding partners, solving a crystal structure of TAPBPR b oth alone and with MHC class I, and assessing functionality of mutated TAPBPR molecules. 3)Investigate the contribution of TAPBPR in infection control and autoimmunity. The role of TAPBPR in infection control will be determined by investigating the susceptibility of TAPBPR knockout mice to viral and bacterial infections. The contribution of TAPBPR in the pathogenesis of the spondyloarthropathies, the strongest autoimmune disease associated with MHC class I, will be determined by comparing t he functionality of TAPBPR variants found in patients to controls on HLA-B27 peptide presentation and immune recognition.
£1,000,000 03 Dec 2014