STUDIES ON REGULATION AND MECHANISM OF HORMONE ACTION

这项研究方案的长期和总体目标是 对激素作用的调节和机制有一定的了解 特别强调甲状腺激素。实现以下目标的一般方法 这个目的是利用自然的错误作为解释的线索。 荷尔蒙作用的正常途径。从这类研究中获得的数据 将不可避免地提供有关可能的治疗方法的信息 荷尔蒙作用的先天缺陷。 给药后组织和代谢反应的测量 对正常人的甲状腺激素的分级剂量将与 甲状腺抵抗综合征患者所获得的抗体 为了建立一种全面、快速的激素(RTH)测定方法 这种情况的诊断。激素受体及其一系列研究进展 成纤维细胞对甲状腺激素的细胞反应 患有RTH的患者将有助于证明假定的异质性 这种综合症的性质。细胞内缺陷的表现应该 导致识别参与正常表达的步骤 甲状腺激素的作用。RTH的发生率及其作为一种 发病原因将使用从以下机构获得的数据确定 甲状腺功能减退症新生儿筛查计划。 对甲状腺激素的摄取、代谢和代谢反应 在已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素，这些因素可能会改变 激素在某些慢性粒细胞白血病患者中的细胞转移和作用 非甲状腺疾病。 甲状腺激素结合球蛋白(TBG)的两种遗传变体，即 在澳大利亚土著人和一些黑人中遇到的将是 调查过了。这些变异型Tbg的分子结构，通过 它们对甲状腺激素亲和力的改变以及它们的微观异质性 等电聚焦模式，将利用生物化学， 免疫学和重组DNA技术。继承的模式，在 具体的X染色体连锁，将被确定。可能的基因 普通型循环TBG的多种物种的来源将是 学习。将在猴子身上研究TBG结构的进化。 已知影响血清总胆红素水平的激素将被用来研究 Hep G2细胞系。它们对总胆红素合成、分泌和分泌的影响 将确定退化，以便了解它们的模式 行动。

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.