This is a competing renewal application, seeking support to continue work with models of murine Graves' disease. Two murine models will be explored: 1) A homologous TSHR immunization model. This version of the Shimojo model uses, instead of immunization with hTSHR-transfected fibroblasts, a homologous system of cell surface-expressed mouse TSHR. 2) A transgenic approach to a Graves' disease model. This model involves the scid/scid transgenic mouse expressing human rather than murine TSHR antigen. These scid-hTSHR mice will be injected with intrathyroidal lymphocytes and engrafted with thyroid tissue from patients with Graves' disease, allowing the human TSHR-Abs to interact with the transgenic human TSHR and induce thyroid overactivity. The applicant believes that the development of both an intact mouse model for Graves' disease as well as the reproduction of the human disease in scid mice will allow a series of interventional procedures to be developed to further the understanding of autoimmune thyroid disease and will provide potential therapeutic approaches to human ATD.
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