Investigators and Projects
In recent years, research has shown that the extra-cellular matrix, far from being the inert scaffolding that it was once considered, is in fact a dynamic structure. Different components interact with each other and with cells, directing growth, activation status, migration and cell death. Among the structural components of the ECM such as fibrin, hyaluronic acid and collagen, many transiently secreted proteins exist. One family of these, the matricellular proteins, has numerous immunomodulatory functions.
Thrombospondin-1 (TSP-1) is an archetypal member of the matricellular family. It is secreted into the matrix, binds to matrix components and to cell surface receptors, but does not play a structural role. TSP-1 is a protein with many functions, achieved by virtue of its multiple domain structure. It is known to bind and activate latent transforming growth factor-beta, to engage CD36 on the surface of endothelial cells and thus inhibit angiogenesis and to inhibit T cell function by binding to CD47.
We have been investigating the role of TSP-1 in autoimmune inflammation, making use of TSP-1 knockout mice. By generating macrophages from these animals and comparing them to those from wild type mice, we have been able to define phenotypic differences that result from a lack of TSP-1 expression. In vivo, it is known that the adult eye makes high levels of TSP-1. This may be important in autoimmune diseases such as experimental autoimmune uveoretinitis (EAU), where we believe the presence or absence of TSP-1 can affect the outcome of disease. If this is the case, this protein may be an appropriate target for new drugs to treat autoimmune disease.
Fordham, J.B., Hua, J., Moorwood, S.R., Schewitz-Bowers, L.P., Copland, D.A., Dick, A.D. & Nicholson, L.B. (2012) Environmental conditioning in the control of macrophage thrombospondin-1 production
Scientific Reports 2, 512; DOI:10.1038/srep00512