STUDIES ON REGULATION AND MECHANISM OF HORMONE ACTION

本研究提案的长期和总体目标是获得 了解激素作用的调节和机制， 特别强调甲状腺激素。 实现的一般方法 这一目标是利用自然界的错误作为阐明 激素作用的正常途径。 从此类研究中获得的数据 将不可避免地提供关于可能的治疗方法的信息， 激素作用的先天缺陷。 测量对施用以下物质的组织和代谢反应： 将对正常个体的甲状腺激素分级剂量进行比较， 在甲状腺抵抗综合征患者中获得的结果 激素（RTH），以建立一个全面和快速的方法， 这种情况的诊断。 激素受体的研究和一些 甲状腺激素的细胞反应在培养的成纤维细胞从 RTH患者将有助于证明假定的异质性 这种综合症的性质。 细胞内缺陷的证明应 导致识别参与正常表达的步骤， 甲状腺激素作用。 RTH的发生率及其作为一种 发病原因将使用从已建立的 新生儿甲状腺功能减退症筛查项目 对甲状腺激素的摄取、代谢和代谢反应将 在建立的人肝癌细胞系（Hep G2）中进行。 这 系统将用于研究血清因子，这些血清因子可能会改变 细胞转移和激素的作用在一些患者 非甲状腺疾病。 甲状腺素结合球蛋白（TBG）的两种遗传变体，即 在澳大利亚原住民和一些黑人中遇到的问题， 研究了 这些变异TBG的分子结构，通过 它们对甲状腺激素的亲和力改变， 等电聚焦模式，将利用生物化学， 免疫学和重组DNA技术。 继承的方式，在 特别是X染色体连锁，将被确定。 可能的基因 常见类型循环TBG的多个物种的起源将是 研究了 将在猴子中研究TBG结构的演变。 将使用以下方法研究已知影响血清TBG水平的激素： Hep G2细胞系。 它们对TBG合成、分泌和 将确定退化，以便了解其模式， 行动上

The long-term and overall objectives of this research proposal are to gain knowledge on the regulation and mechanisms of hormone action, with particular emphasis on thyroid hormone. The general approach to achieve this goal is to exploit the errors of nature as clues for the elucidation of the normal pathways of hormone action. Data obtained from such research would inevitably provide information on possible therapeutic approaches in inborn defects of hormone action. Measurements of tissue and metabolic responses to the administration of graded doses of thyroid hormone to normal individuals will be compared to those obtained in patients with the syndrome of resistance to thyroid hormone (RTH) in order to establish a comprehensive and rapid method for the diagnosis of this condition. Studies on hormone receptor and a number of cellular responses to thyroid hormone in cultured fibroblasts from patients with RTH will serve to demonstrate the presumed heterogeneous nature of this syndrome. Demonstration of intracellular defects should lead to the identification of steps involved in the normal expression of thyroid hormone action. The incidence of RTH and thus its importance as a casue of morbidity will be determined using data obtained from established neonatal screening programs for hypothyroidism. Uptake, metabolism and metabolic responses to thyroid hormone will be carried out in an established human hepatoma cell line (Hep G2). This system will serve to study serum factors which presumably alter the cellular transfer and action of the hormone in some patients with non-thyroidal illnesses. Two genetic variants of thyroxine-binding globulin (TBG), namely that encountered in Australian Aborigines and in some Blacks will be investigated. The molecular structure of these variant TBGs, identified by their altered affinity to thyroid hormone and by their microheterogeneous pattern on isoelectric focusing, will be studied utilizing biochemical, immunologic and recombinant DNA techniques. The pattern of inheritance, in particular X-chromosome linkage, will be determined. The possible genetic origin of the multiple species of common type of circulating TBG will be studied. The evolution of the structure of TBG will be studied in monkeys. Hormones known to affect the serum level of TBG will be studied utilizing the Hep G2 cell line. Their effect on TBG synthesis, secretion and degradation will be determined in order to gain knowledge on their mode of action.