SUMMARY The thyroidal TSH receptor (TSHR) is the major control point for thyroid hormone synthesis and release as well as thyroid growth and development and is also expressed in a wide variety of non- thyroid tissues including adipocytes, fibroblasts, osteoclasts, osteoblasts and immune cells. The TSHR is a major antigen in autoimmune thyroid disease, especially Graves' disease. However, the mechanisms by which the TSHR modulates non-thyroidal cells is largely unclear and the autoimmune role of extra-thyroidal TSHRs mostly unknown. In this submission, we intend to explore the detailed biology and immune role of selected extra-thyroidal TSHRs aided by our extensive experience with TSHR analysis in thyroid cells. We have 3 specific aims: Specific Aim 1- Explore the molecular characterization, posttranslational processing and receptor routing of TSHRs in extra-thyroidal human cells. Specific Aim 2- Examine the promiscuity of heterologous receptor interactions and study TSHR transactivation. Specific Aim 3- Analyze the immunoreactivity of extra thyroidal TSHRs Although the thyroidal TSHR has been extensively explored, the recognition of extra-thyroidal TSHR expression has revealed a large gap in our knowledge. Information already generated suggests that such sites are active and modulate receptor biology and disease as our studies on bone cells and TSHR-KO mice have illustrated. However, concerns that such TSHRs are immunologically suppressed remain unexplored. Large gaps in our knowledge of the receptor biology of these extra thyroidal tissues exist and our studies will begin to clarify some of these questions.