Mechanisms by which fibroblasts from different origins modify the transendothelial recruitment of T-cells and their retention in inflammed tissue. (360G-Wellcome-077828_Z_05_Z)
Our key goal is to show how the recruitment of T-lymphocytes through vascularendothelium and subsequent retention in tissue might be modifed by stromal cells, particularly synovial fibroblasts from patients with rheumatoid arthritis. We suggest that there is a variable stromal 'postcode' whereby fibroblasts in different regions influence the development of inflammation by virtue of their patterns of gene expression, e.g., for chemokines and growth factors. This leads to the hypothesis that fibroblasts fulfill an important regulatory function which becomes modified in chronic inflammatory disorders, causing lack of control of the deposition of T-cells in tissue. We will use endothelial-fibroblast co-culture systems developed in Birmingham, to examine time courses of adhesion and migration of T-cell subsets on endothelial monolayers, and movement through sub-endothelial layers of fibroblasts. These models will incorporate delivery of T-cells from flow and stimulation with cytokines where appropriate. Fibroblasts from different sources will be compared. Based on variations in recruitment and retention ofT-cells, we will disect gene expression and production of cytokines and chemokines, to identify mediators of differential responses. We will test theroles of candidate mediators using blocking strategies. Thus, we aim to identify critical factors affecting 'resolution' of normal and disrupted inflammatory processes.
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Grant Details
Amount Awarded | 199177 |
Applicant Surname | Nash |
Approval Committee | Physiological Sciences Funding Committee |
Award Date | 2005-11-07T00:00:00+00:00 |
Financial Year | 2005/06 |
Grant Programme: Title | Project Grant |
Internal ID | 077828/Z/05/Z |
Lead Applicant | Prof Gerard Nash |
Other Applicant(s) | Prof Christopher Buckley, Prof George Rainger |
Partnership Value | 199177 |
Planned Dates: End Date | 2008-12-31T00:00:00+00:00 |
Planned Dates: Start Date | 2006-01-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | West Midlands |