Graves' ophthalmopathy (GO) is an autoimmune eye disorder closed associated with Graves' hyperthyroidsim. There is convincing experimental evidence that the orbital fibroblast (including the preadipocyte fibroblast subpopulation) is the target cell in GO. However, the autoantigen against which the immune response is directed is unknown. The thyrotropin receptor (TSHr) is a prime candidate to be the orbital autoantigen because its involvement would help to explain the close clinical and laboratory associations between GO and hyperthyroidism. In recent studies, the PI has demonstrated the present of TSHr mRNA and protein in orbital adipose/connective tissues from patients with GO, wile TSHr expression was not apparent in normal orbital tissues. In addition, she showed that orbital preadipocyte fibroblasts, cells lacking fucntional TSHr, can be differentiated in vitro into mature TSHr-bearing adipocytes. These and other findings led to hypothesize that: 1)expression of TSHr in the orbit in GO is linked to the induction of adipogenesis in orbital preadipocyte fibroblasts, and that; 2) the adipocyte TSHr is the orbital autoantigen recognized by orbital-infiltrating lymphocytes in GO. The PI plans to examine these hypotheses using our system of cultured orbital preadipocyte fibroblasts derived from pateints with GO.
In specific aim I, she will define the fibroblast-like cells present in the orbit in GO and identify factors that modulate adipogenesis in these cells. Experiments in Aim II are designed to characterize the obital TSHr and to clarify the link between TSHr expression and adipogenesis in the orbi.
In Aim III, she will determine whether cloned orbital-infiltrating lymphocytes from patients with GO recognize TSHr, or other antigens that are processed """"""""naturally"""""""" by autologous antigen-presenting cells. The main goal of the research program is to increase understanding of the orbital immune response in GO in order that novel and more specific therapeutic and preventive strategies for this condition might be developed.
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