THYROXINE-PROTEIN INTERACTION

甲状腺素-蛋白质相互作用

• 批准号: 3226543
• 负责人: JACK H OPPENHEIMER
• 金额: $ 40.01万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-03-01 至 1992-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3226543
• 关键词: adipose tissue; cell nucleus; chromatography; circadian rhythms; density gradient ultracentrifugation; electrofocusing; gel electrophoresis; genetic regulation; genetic transcription; glucagon; hormone metabolism; hormone receptor; hormone regulation /control mechanism; human subject; hypercholesterolemia; hypothyroidism; laboratory rabbit; laboratory rat; liver metabolism; messenger RNA; nucleic acid sequence; pituitary gland; protein biosynthesis; protein structure; radioimmunoassay; thyroid disorder; thyroid function; thyroid hormone binding protein; tissue /cell culture; triiodothyronine; adipose tissue; cell nucleus; chromatography; circadian rhythms; density gradient ultracentrifugation; electrofocusing; gel electrophoresis; genetic regulation; genetic transcription; glucagon; hormone metabolism; hormone receptor; hormone regulation /control mechanism; human subject; hypercholesterolemia; hypothyroidism; laboratory rabbit; laboratory rat; liver metabolism; messenger RNA; nucleic acid sequence; pituitary gland; protein biosynthesis; protein structure; radioimmunoassay; thyroid disorder; thyroid function; thyroid hormone binding protein; tissue /cell culture; triiodothyronine

In the proposed grant period, we shall continue efforts to define the mechanism of thyroid hormone action at the cellular level. Emphasis will be placed on an elucidation of the nature and function of hepatic S14, a protein coded buy an mRNA which is rapidly responsive to thyroid hormone and carbohydrate administration. We shall attempt to define the nature the factors which regulate the expression of the gene for S14 and determine the basis of marked circadian variation of its mRNA. We plan to isolate the protein, define its subcellular localization, and deduce its function in a broken cell preparation. We shall attempt to determine to what extent T3 induces specific mRNA's by augmenting gene transcription or by stabilizing the mature or precursor mRNA. We shall extend ongoing studies demonstrating DNAse hypersensitive sites in those rat tissues which respond to T3 with an induction of mRNAS14. Efforts will be made to identify the specific nuclear proteins which may be responsible for the creation of the hypersensitive sites. In conjunction with these experiments, we propose renewed efforts to isolate the T3- nuclear receptor and determine the precise role of this protein in the initiation mechanism. Appropriate comparisons will be made between the hepatic mechanism under study in this laboratory and T3 induction of the mRNA for growth hormone in the pituitary. Such studies should help to reconcile apparent differences in the induction mechanism as inferred from recent reports (transcription vs. RNA stabilization; requirement for ongoing protein synthesis). We shall also try to develop a wider spectrum of model systems for the study of thyroid hormone action at the cellular level. We shall examine the effects of T3 on fat and the central nervous system using both two-dimensional mRNA activity profiles and hybridization techniques. Lastly, we are planning to continue ongoing clinical studies designed to define the plasma hormone signal responsible for pituitary suppression in man. Further , we shall apply the techniques of two-dimensional mRNA profiling to analyze the level and patterns of high abundancy sequences in human mononuclear cells derived from patients with thyroidal disease and patients with nonthyroidal catabolic disorders who exhibit lowered levels of circulating thyroid hormones. Such studies may reveal the physiological significance of the "low-T3 state".

在拟议的赠款期内，我们将继续努力定义 甲状腺激素在细胞水平上作用的机制。 重点将放在阐明自然和 肝S14的功能，一种编码的蛋白质购买mRNA 快速响应甲状腺激素和碳水化合物 行政。 我们将尝试定义因素 调节S14基因的表达并确定 其mRNA的昼夜节律变化的基础。 我们计划 隔离蛋白质，定义其亚细胞定位并推断 它在破裂的细胞制备中的功能。 我们将尝试 确定T3在多大程度上通过 增强基因转录或稳定成熟或 前体mRNA。 我们将扩展正在进行的研究证明 那些大鼠组织中的DNase超敏部位 T3具有MRNAS14的诱导。 将努力 确定可能负责的特定核蛋白 为了创建高度敏感地点。 结合 这些实验，我们提出了新的努力来隔离T3- 核受体并确定该蛋白在 启动机制。 将进行适当的比较 在该实验室研究的肝机制和 T3诱导垂体中生长激素的mRNA诱导。 这样的研究应有助于调和明显的差异 从最近的报告中推断出的归纳机制 （转录与RNA稳定； 蛋白质合成）。 我们还将尝试开发更广阔的范围 用于研究甲状腺激素作用的模型系统 细胞水平。 我们将检查T3对脂肪和脂肪的影响 使用二维mRNA的中枢神经系统 活动曲线和杂交技术。 最后，我们是 计划继续旨在定义的临床研究 血浆激素信号负责垂体抑制 男人。 此外，我们将应用二维技术 mRNA分析以分析高的水平和模式 人类单核细胞中的丰富序列 患有甲状腺疾病的患者和非甲状腺功能障碍患者 表现出较低循环水平的分解代谢疾病 甲状腺激素。 这样的研究可能揭示了生理 “低T3状态”的意义。