The objective of the proposed research is to gain a better understanding of the regulation of retroocular and endomysial connective tissue. Those tissues occupy an increased volume in the ophthalmopathy associated with Graves' disease and an accumulation of glycosaminoglycan in the retroocular space apparently accounts for the exophthalmos. We have found that hyaluronate synthesis is stimulated by interferon gamma in cultured retroocular and endomysial fibroblasts but not those derived from skin or breast adipose tissue. 1) We propose to characterize the stimulation by interferon gamma of hyaluronate synthesis in retroocular and endomysial fibroblasts. 2) We propose to study the effects of interferon gamma on the phosphorylation pattern of proteins in orbital fibroblast cultures. We will present preliminary data which suggest that the cytokine enhances phosphorylation of proteins in orbital fibroblast cultures but not in non-orbital cultures. We hypothesize that the stimulation of hyaluronate synthesis by interferon gamma is mediated through an activation of a kinase cascade. 3) We propose to determine whether lymphocytes cultured from individuals with Graves' ophthalmopathy produce increased amounts of interferon gamma. We hypothesize that if that cytokine has a role in the pathogenesis of Graves' ophthalmopathy, we may be able to detect increased interferon gamma production when compared to lymphocytes from individuals without Graves' disease. 4) We propose to determine whether a positive correlation exists between the serum concentration of interferon gamma and the clinical severity of Graves' ophthalmopathy. We present evidence that the serum concentration of that cytokine is elevated in some individuals with active Graves' disease.
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