THYROTROPIN AND ITS RECEPTOR

促甲状腺素及其受体

• 批准号: 3463986
• 负责人: JOHN C. MORRIS
• 金额: $ 9.19万
• 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/3463986
• 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TSH的一级结构以及 类似的促性腺激素LH，FSH和hCG，已经确定，这三个 激素的空间结构及其细节 结构-功能关系仍然未知。 目前的证据 表明，几个激素位点参与了 促甲状腺激素及其受体和网站涉及两个促甲状腺激素特异性 β-亚基和α-亚基，这是共同的所有四个 荷尔蒙 我们最近的研究，使用合成肽的方法， 在共同的α-亚基中确定了两个区域， 具有促甲状腺激素受体结合活性的β-TSH。 的 代表这些序列的合成肽不是激素 激动剂，但在生物测定中证明是完整激素的拮抗剂 抑制甲状腺刺激活性 免疫球蛋白（TSI）是甲状腺功能亢进症的原因观察 Graves'病患者的情况。 在本申请中，我提出： 1)研究hTSH的结构与功能关系 α-亚基，并进一步鉴定α-亚基的特异性残基。 亚基甲状腺特异性结合和可能的生物活性， 合成肽策略; 2）开发特异性TSH抑制剂， 取代、缺失和/或化学修饰 鉴定的活性氨基酸残基; 3）使用类似的合成 多肽法在新近克隆的人TSH受体研究中的应用 （hTSHr）以鉴定受体的特定区域， 参与激素结合;以及4）鉴定所述抗体的表位。 抗Graves病患者hTSHr的自身抗体 使用为上述目的产生的合成受体肽治疗疾病 （三）、 促甲状腺激素抑制剂的开发， 合成肽对受体自身表位的影响应 被认为是向特异性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。