The long-term objective of this proposal is to determine the role of fibroblast heterogeneity in the pathogenesis of Graves ophthalmopathy (GO). GO is an autoimmune process associated with lymphocyte and mast cell recruitment resulting in hyaluronan deposition and inflammation of the orbit. This laboratory has demonstrated that orbital fibroblasts exhibit phenotypic attributes that distinguish them from other fibroblasts. The hypothesis to be tested in this proposal is that exaggerated responses of orbital fibroblasts to pro-inflammatory cytokines and CD40 activation by its ligand (CD40L) in fibroblast subsets represent the molecular basis of GO. Populations of orbital fibroblasts subsetted according to Thy-1 expression or its absence both display surface CD40 but exhibit distinct metabolic characteristics. Moreover, CD40 activation by CD40L enhances IL-6 and IL-8 expression. Data presented in this application support the concept that CD40 expression represents a major signal conduit for orbital fibroblast activation by T lymphocytes and mast cells.
The specific aims are as follows: 1) determine whether the exaggerated up-regulation of hyaluronan synthesis by cytokines occurs predominantly in one fibroblast subset by quantitating macromolecular synthesis and HAS (the putative hyaluronan synthase) mRNA expression in pure Thy-1+ and THY-1- orbital subsets; 2) determine whether induction of cyclooxygenase-2 and PGE2 production by pro-inflammatory cytokines can be attributed to one of these fibroblast subsets and 3) determine how widely CD40 activation in orbital fibroblast subsets alters the expression of cytokines, cyclooxgenase, hyaluronan and collagen synthesis. Results derived from this project may lead to the development of new therapeutic strategies for GO and other inflammatory processes in the orbit and perhaps in other tissues.
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