TSH RECEPTOR AUTOREGULATION

TSH 受体自动调节

• 批准号: 9037499
• 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 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9037499
• 关键词: Adipocytes; Animal Model; Anterior Pituitary Gland; Antigens; Applications Grants; Arrestins; Cell Line; Cell membrane; Cells; Complex; Development; Dimerization; Disease; Epithelial Cells; Fatty acid glycerol esters; Fibroblasts; GTP-Binding Proteins; Genes; Genetic; Goiter; Growth and Development function; Hashimoto Disease; Homeostasis; Hot Nodule; Human; Immune system; Knowledge; Laboratories; Learning; Link; Malignant Neoplasms; Malignant neoplasm of thyroid; Messenger RNA; Molecular; Mutation; Nodule; Pattern; Physiology; Population; Post-Translational Protein Processing; Protein Isoforms; RNA Splicing; Receptor Activation; Reporter; Role; Secondary to; Signal Transduction; Site; Somatic Mutation; Structure; Techniques; Thyroid Diseases; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyroid Nodule; Thyrotropin; Thyrotropin Receptor; Tissues; Trans-Activators; Transcript; Variant; Veterans; Work; autoimmune thyroid disease; bone; bone cell; dimer; functional status; human disease; monomer; public health relevance; receptor; receptor function; thyroid associated ophthalmopathies

DESCRIPTION (provided by applicant): Thyrotropin (TSH) comes from the anterior pituitary gland and is the major controlling factor for the development and function of the thyroid gland which is the essential supplier of thyroid hormone to the entire body. TSH works on the thyroid gland through the TSH receptor (TSHR) which is a complex molecule expressed on the thyroid cells as well as on a variety of non-thyroid tissues including fat and bone. The TSHR is also a major site of attack by the immune system in some common diseases such as Hashimoto's thyroiditis and Graves' disease and becomes overactive in what we call "hot" thyroid nodules causing thyroid over-activity. The TSH receptor is also involved in thyroid cancer since in animal models the lack of the receptor dampens the propensity for cancer development. The complexity of the TSH receptor is further enhanced by the fact that it has a variety of structures secondary to the formation of variants following RNA splicing. However, the splicing repertoire of the TSH receptor has not been well characterized since our early description of what we call variant 1.3. Although we know that increased diversity of cell signaling options at the receptor can be enhanced by increased numbers of receptor forms, the functional consequences of TSH receptor splicing, cleavage and multimerization in the thyroid and in non-thyroid tissues remains incomplete. Hence, the aims of the proposed study are: (1) To characterize TSH receptor variants in normal and pathological tissues and their role in modulating receptor function. (2) To examine the influence of stimulating the TSH receptor on the variants and multimers. (3) To identify TSH receptor variants and multimer formation in non-thyroidal tissues. This grant proposal is to advance our understanding of the structure and function of the TSH receptor variants and to see how they influence signal bias and diversity through multimerization. This knowledge will help us understand the role of the TSH receptor in a variety of thyroid disorders including thyroid nodules, thyroid cancer and autoimmune thyroid disease.

描述（由申请人提供）： 促甲状腺素（TSH）来自垂体前叶，是甲状腺发育和功能的主要控制因素，是全身甲状腺激素的重要供应者。 TSH 通过 TSH 受体 (TSHR) 对甲状腺起作用，TSHR 是一种在甲状腺细胞以及各种非甲状腺组织（包括脂肪和骨骼）上表达的复杂分子。 TSHR 也是桥本甲状腺炎和格雷夫斯病等一些常见疾病中免疫系统攻击的主要部位，并且在我们所说的“热”甲状腺结节中变得过度活跃，导致甲状腺过度活跃。 TSH 受体也与甲状腺癌有关，因为在动物模型中，缺乏该受体会抑制癌症发展的倾向。 TSH 受体的复杂性进一步增强，因为它具有多种继发于 RNA 剪接后形成变体的结构。然而，自从我们早期描述所谓的变体 1.3 以来，TSH 受体的剪接功能尚未得到很好的表征。尽管我们知道受体形式数量的增加可以增强受体细胞信号传导选项多样性的增加，但甲状腺和非甲状腺组织中 TSH 受体剪接、裂解和多聚化的功能后果仍然不完整。因此，本研究的目的是：（1）表征正常和病理组织中的TSH受体变异及其在调节受体功能中的作用。 (2)考察刺激TSH受体对变异体和多聚体的影响。 (3) 鉴定非甲状腺组织中的 TSH 受体变异和多聚体形成。 这项拨款提案旨在增进我们对 TSH 受体变体的结构和功能的理解，并了解它们如何通过多聚化影响信号偏差和多样性。这些知识将帮助我们了解 TSH 受体在多种甲状腺疾病中的作用，包括甲状腺结节、甲状腺癌和自身免疫性甲状腺疾病。