The long-term objective of this application is to identify the unique phenotypic attributes of orbital fibroblasts that underlie their exaggerated responses to pro-inflammatory mediators. The hypothesis tested is that these attributes are responsible for the dramatic inflammation and hyaluronan accumulation seen in thyroid-associated ophthalmopathy (TAO). T lymphocytes and mast cells infiltrate the orbit in TAO and are believed to elaborate cytokines that drive the tissue remodeling. Some of these responses are mediated through intermediate induction of IL-lalpha including up-regulation of prostaglandin endoperoxidase H synthase-2 (PGHS-2) and hyaluronan synthase-2 (HAS2). TAO fibroblasts exhibit a deficient induction of IL-1 receptor antagonist (IL-1ra) which ordinarily modulates IL-1 action. The investigator hypothesizes that this underlies at least some of the exaggerated cellular responses. TAO fibroblasts unlike normal cells respond to IgG from patients with TAO to produce IL-16, a CD4+ specific chemoattractant. This induction can be blocked with the macrolide, rapamycin, implying that the FRAP/mTor pathway might be involved. The investigator now proposes to 1) identify the basis for disordered hyaluronan accumulation by determining the mechanism for HAS2 induction in orbital fibroblasts and map the human HAS2 promoter cloned recently by us; 2) determine the basis for the defective IL-1ra induction by comparing IL-1ra mRNA and protein levels, gene transcription, promoter activity and transcript stability in TAO and normal fibroblasts; 3) determine the rapamycin-sensitive signaling pathways mediating IL-16 induction by TAO lgG in affected fibroblasts and how to block them. It is believed that the insights derived from this project will allow the formulation of specific therapeutic strategies for interrupting the pathogenesis of TAO.
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