RENAL THYROID HORMONE UPTAKE & DEIODINATION

这项建议的长远目标，是研究 调节外周组织对甲状腺素（T4）的摄取， 甲状腺的产物，以及随后的5 '-脱碘， 3，5，3 '-三碘甲状腺原氨酸（T3），最有效的甲状腺激素，和 5-脱碘为3，3 '，5'三碘甲状腺原氨酸（rT 3），一种甲状腺激素 非活性产品。 具体而言，将强调 肾脏在全身产生T3。 使用已建立的肾脏灌注方法以及质膜 T4和T3的肾脏摄取和脱碘机制 将被定性。 脱碘位点将在功能上 相对于灌流中管状碘化物处理的部位， 肾 将完成甲状腺激素代谢物的测量 用放射免疫测定技术和高压液体 放射性示踪剂化合物的色谱（HPLC）分析。 的 灌注器官系统提供了研究甲状腺激素的机会 在完整器官中的代谢，这是从混杂的 其他组织的影响。 此外，灌注的器官可能 能够对激素和基质刺激作出反应。 糖尿病患者肾功能下降的调节机制 将进一步探讨。 另外，灌注的肾脏 rT 3的产生和降解将与其T3的产生进行比较。 膜稳定剂和有机阴离子对甲状腺功能的影响 将检查激素摄取和代谢。 流入和流出速率 甲状腺激素的变化将被用来表征肾脏的变化， 保留这些化合物。 细胞溶质结合将与 代谢改变后器官对碘甲腺原氨酸摄取的变化 状态和某些药物的治疗。 鲁米那制剂和 对腔肾质膜囊泡将用于研究 在这些网站的相对5 '-脱碘率，以及探索 存在碘甲腺原氨酸和碘化物的膜转运系统。 这些研究将有助于了解单个器官 甲状腺激素的摄取和代谢及其与甲状腺激素的关系 作用和可能改变拟甲状腺活性的潜在步骤 在细胞水平上。

The long term objective of this proposal is to study the factors which regulate the peripheral tissue uptake of thyroxine (T4), the main secretory product of the thyroid gland, and subsequent 5'-deiodination to 3,5,3'-triiodothyronine (T3), the most potent thyroid hormone, and 5-deiodination to 3,3',5' triiodothyronine (rT3), a thyromimetically inactive product. Specifically, emphasis will be placed on the role of the kidney in the whole body production of T3. Using an established method of kidney perfusion, as well as plasma membrane preparations, the mechanisms of renal uptake and deiodination of T4 and T3 will be characterized. The locus of deiodination will be functionally identified relative to the site of tubular iodide handling in the perfused kidney. Measurements of thyroid hormone metabolites will be accomplished both with radioimmunoassay techniques and with high pressure liquid chromatographic (HPLC) analysis of radioactive tracer compounds. The perfused organ system provides the opportunity to study thyroid hormone metabolism in an intact organ which is separation from the confounding effects of other tissues. In addition, the perfused organ is potentially able to respond to hormonal and substrate stimuli. The mechanisms regulating the decreased renal production during diabetes mellitus will be further explored. In addition, the perfused kidney's production and degradation of rT3 will be compared with its T3 production. The effect of membrane-stabilizing drugs and organic anions on thyroid hormone uptake and metabolism will be examined. Rates of influx and efflux of thyroid hormone will be used to characterize changes in the renal retention of these compounds. Cytosolic-binding will be correlated with changes in organ uptake of iodothyronines after alterations in metabolic state and therapy with certain drugs. Preparations of luminal and contraluminal renal plasma membrane vesicles will be used to study the relative 5'-deiodination rates at these sites as well as to explore the existence of membrane transport systems for iodothyronines and iodide. These studies will contribute to the understanding of individual organ thyroid hormone uptake and metabolism, its relation to thyroid hormone action, and potential steps at which thyromimetic activity may be modified at the cellular level.