The overall objective of this proposal is to understand the role of orbital fibroblasts in the pathogenesis of thyroid-associated ophthalmopathy (TAO), the orbital manifestation of Graves' disease (GD). There are currently no effective therapies for this potentially sight-threatening disease. We have found that GD fibroblasts express excessive levels of insulin-like growth factor-1 receptor (IGF-1R), which is activated by GD-specific antibodies (GD-IgG). This leads to expression ofIL-16 and RANTES, two T lymphocyte chemo attractants. Moreover, GD-IgG provokes the nuclear accumulation of lGF-1Ralpha, in GD fibroblasts. Control fibroblasts fail to respond to GD-IgG. We hypothesize that IGF-1R activation by GD-IgG and consequent induction oflL-16 and RANTES underlie T cell infiltration of the orbit and other connective tissue in GD. On the other hand, orbital fibroblasts exhibit unique phenotypic attributes, including exaggerated responses to cytokines such as IL-1beta. These include the induction oflL-6, an important B cell activator and enzymes for hyaluronan and PGE2 production. We hypothesize that hyaluronan, PGEe and IL-6 synthesis by orbital fibroblasts leads to localized orbital manifestations of TAO. We propose to 1) define the molecular events surrounding the activation of lGF-1R by GD-IgG and the resulting signaling that leads to IL-16 and RANTES expression by studying IGF-1R expression, and signaling and characterizing the GD-IgG/IGF- 1R interactions 2) characterize the anatomic site-specific induction in orbital fibroblasts of IL-6 by IL-1beta by assessing gene transcription, mRNA stability, and signal transduction 3) assess the expression and induction by IL-1beta of phospholipase A2 (sPLA2 and cPLAz) in orbital fibroblasts by determining whether gene transcription and/or mRNA stability are involved and whether PLA2 expression and activity influences levels of other key prostanoid biosynthetic enzymes. Our results to date, we believe, represent a new disease paradigm for TAO. Moreover, the proposed studies represent logical extensions of our recent findings and should lead to the identity of mechanism-based therapeutic targets for this vexing disease.
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