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; 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）： 甲状腺激素（TSH）来自垂体前腺，是甲状腺发育和功能的主要控制因素，甲状腺的发育和功能是甲状腺激素对整个身体的重要供应商。 TSH通过TSH受体（TSHR）在甲状腺上起作用，TSH受体（TSHR）是在甲状腺细胞以及包括脂肪和骨骼在内的多种非甲状腺组织上表达的复杂分子。 TSHR也是免疫系统在某些常见疾病中的主要攻击部位，例如桥本甲状腺炎和坟墓的疾病，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受体也参与甲状腺癌，因为在动物模型中，缺乏受体会抑制癌症发展的倾向。 TSH受体的复杂性通过以下事实进一步增强：它具有继承RNA剪接后变体形成的多种结构。但是，自从我们对变体1.3的早期描述以来，TSH受体的剪接曲目尚未得到很好的特征。尽管我们知道，受体形式的数量增加，可以增强受体细胞信号选项的多样性，但甲状腺和非甲状腺组织中TSH受体剪接，裂解和多聚体的功能后果仍然不完整。因此，拟议的研究的目的是：（1）表征正常和病理组织中TSH受体变体及其在调节受体功能中的作用。 （2）检查刺激TSH受体对变体和多聚体的影响。 （3）鉴定非甲状腺组织中的TSH受体变体和多聚体的形成。 该赠款提案是为了促进我们对TSH受体变体的结构和功能的理解，并通过多聚化来了解它们如何影响信号偏见和多样性。这些知识将有助于我们了解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。