TSH RECEPTOR AUTOREGULATION

描述(由申请人提供)： 促甲状腺激素(TSH)来自于脑下垂体前叶，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)作用于甲状腺，TSHR是一种复杂的分子，表达在甲状腺细胞以及包括脂肪和骨骼在内的各种非甲状腺组织上。在桥本氏甲状腺炎和格雷夫斯病等常见疾病中，TSHR也是免疫系统攻击的主要部位，并在我们所称的“热”甲状腺结节中变得过度活跃，导致甲状腺过度活动。促甲状腺激素受体也与甲状腺癌有关，因为在动物模型中，受体的缺乏抑制了癌症的发生。TSH受体的复杂性进一步增加了这一事实，即它具有多种结构，其次是RNA剪接后形成的变体。然而，自从我们早期描述了我们所说的变体1.3以来，TSH受体的剪接谱系还没有得到很好的表征。尽管我们知道，受体形式的增加可以增加细胞信号选择的多样性，但TSH受体在甲状腺和非甲状腺组织中的剪接、切割和多聚体的功能结果仍然不完整。因此，本研究的目的是：(1)研究TSH受体在正常组织和病理组织中的变异及其在调节受体功能中的作用。(2)检测刺激TSH受体对突变体和多聚体的影响。(3)鉴定非甲状腺组织中TSH受体的变异和多聚体的形成。这项资助建议是为了促进我们对TSH受体变异体的结构和功能的理解，并了解它们如何通过多聚体影响信号偏向和多样性。这些知识将帮助我们了解TSH受体在包括甲状腺结节、甲状腺癌和自身免疫性甲状腺疾病在内的各种甲状腺疾病中的作用。

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.