TSH RECEPTOR AUTOREGULATION

摘要 甲状腺促甲状腺激素受体(TSHR)是甲状腺激素合成和分泌的主要控制点。 释放以及甲状腺的生长和发育，也表达在各种各样的非 甲状腺组织包括脂肪细胞、成纤维细胞、破骨细胞、成骨细胞和免疫细胞。这个 TSHR是自身免疫性甲状腺疾病，尤其是Graves病的主要抗原。然而， TSHR调节非甲状腺细胞的机制在很大程度上还不清楚，而且 甲状腺外TSHR的自身免疫作用大多未知。在本意见书中，我们打算 探索由OUR辅助的精选甲状腺外TSHR的详细生物学和免疫作用 丰富的甲状腺细胞TSHR分析经验。我们有三个具体目标： 具体目标1-探索分子表征、翻译后加工 以及TSHR在甲状腺外人类细胞中的受体路径。 具体目标2-检查异源受体相互作用和 研究TSHR的反式激活。 特定目标3-分析甲状腺外TSHR的免疫反应性 虽然甲状腺TSHR已经得到了广泛的探索，但对甲状腺外TSHR的认识 TSHR的表达揭示了我们知识中的巨大差距。已生成的信息 这表明这些位点是活跃的，并调节受体生物学和疾病，正如我们对 骨细胞和TSHR-KO小鼠已经证明。然而，人们担心这样的TSHR是 免疫抑制仍未被发现。我们对受体的认识存在很大差距 这些额外的甲状腺组织的生物学存在，我们的研究将开始澄清其中的一些 问题。

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.