THYROTROPIN AND ITS RECEPTOR

促甲状腺素及其受体

• 批准号: 3463988
• 负责人: JOHN C. MORRIS
• 金额: $ 10.69万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-06-01 至 1996-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3463988
• 关键词: Graves disease; active immunization; animal tissue; autoantibody; autoimmune disorder; bioassay; cow; dogs; enzyme linked immunosorbent assay; glycoprotein structure; hormone receptor; human subject; human tissue; immunological substance; laboratory mouse; laboratory rabbit; peptide chemical synthesis; protein structure function; radioimmunoassay; receptor binding; synthetic peptide; thyrotropin; tissue /cell culture

Although the primary structure of human TSH as well as the structurally similar gonadotropins LH, FSH, and hCG, has been determined, the three dimensional structure of the hormone and the details of its structure-function relationships remain unknown. Current evidence suggests that several hormone sites are involved in the interaction of TSH with its receptor and that the sites involve both the TSH specific beta-subunit as well as the alpha-subunit that is common to all four hormones. Our recent studies, using a synthetic peptide approach, identified two regions within the common alpha-subunit and four regions of beta-TSH that possess binding activity for TSH receptors. The synthetic peptides representing these sequences were not hormone agonists, but proved to be antagonists of the intact hormones in bioassay and also inhibited the bioactivity of the thyroid stimulating immunoglobulins (TSI) that are the cause of the hyperthyroidism observed in patients with Graves' disease. In the current application I propose: 1) to study the structure-function relationships of the hTSH alpha-subunit and to identify further the specific residues of the subunit that thyroid specific binding and perhaps bioactivity using a synthetic peptide strategy; 2) to develop specific inhibitors of TSH by substitution, deletion, and/or chemical modification of the above identified active amino acid residues; 3) to use a similar synthetic peptide approach in the study of the recently cloned human TSH receptor (hTSHr) in order to identify the specific regions of the receptor that are involved in hormone binding; and 4) to identify the epitope for the auto-antibodies directed against the hTSHr found in patients with Graves' disease using the synthetic receptor peptides generated for the above aim (3). Both the development of inhibitors of TSH, and the identification of the auto-epitope of the receptor by the synthetic peptide should be considered important first steps in the direction of specific immune therapy of autoimmune thyroid disease.

虽然人促甲状腺激素的一级结构以及结构 类似的促性腺激素黄体生成素、卵泡刺激素和人绒毛膜促性腺激素已经被检测出来，这三种 荷尔蒙的空间结构及其细节 结构与功能的关系仍然未知。现有证据 提示多个荷尔蒙部位参与了 TSH和它的受体，并且这些位点涉及TSH特异性的 β亚基和阿尔法亚基，这四个亚基都是共同的 荷尔蒙。我们最近的研究，使用了一种合成肽的方法， 确定了共同的阿尔法亚单位内的两个区域和四个区域 具有与TSH受体结合活性的β-TSH。这个 代表这些序列的合成肽不是激素 激动剂，但经生物测定证明是完整激素的拮抗剂 还抑制了生物活性对甲状腺的刺激作用 免疫球蛋白(TSI)是所观察到的甲状腺功能亢进症的原因 在格雷夫斯病患者身上。在目前的申请中，我建议： 1)研究HTSH的结构-功能关系 并进一步鉴定α-亚基的特定残基 该亚单位与甲状腺特异结合，并可能使用 合成肽策略；2)通过以下途径开发TSH特异性抑制剂 上述的替换、删除和/或化学修饰 鉴定的活性氨基酸残基；3)使用类似的合成 多肽技术在新近克隆的人促甲状腺激素受体研究中的应用 (HTSHr)为了识别受体的特定区域， 参与激素结合；以及4)确定 在Graves病患者中发现针对hTSHr的自身抗体 疾病使用为上述目的产生的合成受体多肽 (3)。促甲状腺激素抑制剂的研究进展及鉴定 合成肽对受体的自身表位的影响应该是 被认为是朝着特定免疫方向迈出的重要第一步 自身免疫性甲状腺疾病的治疗。