The basis of autoimmune thyroid disease remains unclear. Apoptosis, the process responsible for thyroid cell death in thyroiditis, has recently been found to be important in the pathogenesis of this disorder. Work from our laboratory and from others indicates that apoptosis is closely regulated in thyroid cells. We have further shown that unique combinations of inflammatory cytokines facilitate the induction of immune-mediated apoptosis in a manner that can permit thyrocyte destruction and the development of hypothyroidism. Based on these findings, we hypothesize that autoimmune inflammation alters the regulation of programmed cell death in thyroid cells leading to destructive thyroiditis and hypothyroidism. Altered apoptosis could contribute to the pathogenesis of thyroiditis either by facilitating immune-mediated apoptosis of thyrocytes or by allowing neighboring thyroid cells to kill each other (fratricide) with this process eventually depleting thyrocytes to cause hypothyroidism. The studies outlined in this proposal seek to examine this hypothesis in four specific aims. The first specific aim will finish documenting the expression and function of regulated proteins that are involved in specific cell-death pathways in thyroid follicular cells. These molecules include pro and anti-apoptotic regulators involved with either specific death receptors or mitochondrial apoptotic pathways. The second specific aim will identify when and to what degree alterations in the regulation of the apoptotic pathways are present in vivo in thyroid cells, as well as alterations in apoptotic regulatory protein trafficking or processing, particularly during the expression of autoimmune disease. The third specific aim will employ animal models to verify that regulatory changes in the cell death pathways lead to thyroid destruction in autoimmune disease. These studies will clarify how thyroid cells are damaged by autoimmune responses and provide new approaches for predicting individuals at risk and developing therapeutic intervention.
Showing the most recent 10 out of 20 publications
