TSH RECEPTOR AUTOREGULATION

TSH 受体自动调节

• 批准号: 10456019
• 负责人: TERRY Francis DAVIES
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456019
• 关键词: Active Sites; Adipocytes; Agonist; Antibodies; Antigens; Autoimmune; Binding; Biology; Bioluminescence; Body part; CRISPR/Cas technology; Cell physiology; Cells; Characteristics; Co-Immunoprecipitations; Cytometry; Development; Disease; Energy Transfer; Eye; Fatty acid glycerol esters; Fibroblasts; Fluorescence; Fluorescence Resonance Energy Transfer; Funding; GTP-Binding Proteins; Graves' Disease; Growth and Development function; Homeostasis; Human; Hyperthyroidism; Immune; Immune response; Immunohistochemistry; Immunologic Receptors; Insulin-Like Growth Factor Receptor; Knockout Mice; Knowledge; Learning; Life Cycle Stages; Ligands; Link; Mainstreaming; Malignant neoplasm of thyroid; Mass Spectrum Analysis; Membrane Microdomains; Messenger RNA; Molecular; Monitor; Muscle; Operative Surgical Procedures; Osteoblasts; Osteoclasts; Pathway interactions; Patients; Phenotype; Phosphorylation; Physiology; Preparation; RNA Splicing; Receptor Gene; Receptor Signaling; Role; Route; Signal Transduction; Site; Skin; Small Interfering RNA; Suspensions; System; TSH receptor antibody; Testing; Thyroid Diseases; Thyroid Gland; Thyroid Hormones; Thyrotropin Receptor; Tissues; Transactivation; Variant; Western Blotting; Woman; antagonist; autoimmune thyroid disease; bone; bone cell; design; dimer; experience; glycosylation; immunoreactivity; inhibitor; men; military veteran; novel; protein activation; receptor; receptor expression; small molecule; src-Family Kinases; thyroid associated ophthalmopathies; trafficking; tumor

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.

概括 甲状腺促甲状腺激素受体（TSHR）是甲状腺激素合成和代谢的主要控制点。 释放以及甲状腺的生长和发育，也以多种非 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 TSHR 是自身免疫性甲状腺疾病，尤其是格雷夫斯病的主要抗原。然而， TSHR 调节非甲状腺细胞的机制在很大程度上尚不清楚，并且 甲状腺外 TSHR 的自身免疫作用大多未知。在本次提交中，我们打算 在我们的帮助下探索选定的甲状腺外 TSHR 的详细生物学和免疫作用 在甲状腺细胞 TSHR 分析方面拥有丰富的经验。我们有 3 个具体目标： 具体目标 1- 探索分子表征、翻译后加工 以及甲状腺外人类细胞中 TSHR 的受体路径。 具体目标 2 - 检查异源受体相互作用的混杂性 研究 TSHR 反式激活。 具体目标 3 - 分析甲状腺外 TSHR 的免疫反应性 尽管甲状腺 TSHR 已被广泛探索，但对甲状腺外甲状腺激素的认识 TSHR 表达揭示了我们知识上的巨大差距。已生成信息 正如我们的研究表明，这些位点是活跃的并调节受体生物学和疾病 骨细胞和 TSHR-KO 小鼠已得到说明。然而，人们担心此类 TSHR 免疫抑制仍有待探索。我们对受体的了解存在巨大差距 这些额外甲状腺组织的生物学特性是存在的，我们的研究将开始阐明其中一些 问题。