RENAL THYROID HORMONE UPTAKE & DEIODINATION

这项建议的长期目标是研究下列因素 调节外周组织摄取主要分泌物甲状腺激素(T4) 甲状腺的乘积，以及随后的5‘-脱碘 3，5，3‘-三碘甲腺原氨酸(T3)，最有效的甲状腺激素，以及 5-脱碘生成3，3‘，5’-三碘甲腺原氨酸(RT3) 不活跃的产品。具体而言，重点将放在 肾脏在全身产生三碘甲腺原氨酸。 使用已建立的肾脏灌流方法以及质膜 T4和T3的制备、肾脏摄取和脱碘机制 将被描述为。脱碘的轨迹将在功能上 确定与灌流中的管状碘处理位置相关的位置 肾脏。将完成对甲状腺激素代谢物的测量 用放射免疫分析技术和高压液体 放射性示踪化合物的高效液相色谱分析。这个 灌流器官系统为研究甲状腺激素提供了机会 从混乱中分离出来的完整器官中的新陈代谢 其他组织的影响。此外，灌流的器官有可能 能够对荷尔蒙和底物刺激做出反应。 糖尿病时肾脏生成量减少的调节机制 糖尿病将得到进一步的研究。此外，灌流的肾脏 RT3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的影响 将检查激素的吸收和新陈代谢。流入和流出速率 甲状腺激素的变化将被用来描述肾脏的变化 保留这些化合物。胞液结合将与 代谢改变后器官对碘甲状腺原氨酸摄取的变化 状态和某些药物的治疗。鲁米那和鲁米那的制剂 对侧肾细胞质膜囊泡将被用于研究 这些站点的相对5‘-脱碘率以及探索 碘甲腺原氨酸和碘的膜转运系统的存在。 这些研究将有助于对单个器官的理解 甲状腺激素摄取代谢及其与甲状腺激素的关系 行动，以及可修改甲状腺似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.