Goumaz M O, Schwartz H, Oppenheimer J H, Mariash C N
Department of Medicine, University of Minnesota, Minneapolis 55455.
Am J Physiol. 1994 Jun;266(6 Pt 1):E1001-11. doi: 10.1152/ajpendo.1994.266.6.E1001.
We found in preliminary experiments that multiple daily injections of triiodothyronine (T3) resulted in an apparent prolongation in the half time (t1/2) of mRNA-S14 decay. To appropriately interpret these observations, we developed a mathematical model of the fluctuations of mRNA-S14 and its nuclear precursor after a single injection or multiple daily injections of T3. The model parameters include 1) the effect of plasma protein binding and metabolic clearance rates on receptor-bound nuclear T3, 2) the threefold circadian variation in mRNA-S14, 3) a 12-min t1/2 for the nuclear precursor and a 1.5-h t1/2 for the mature mRNA-S14, 4) previously derived relationships between the level of plasma T3 and nuclear occupancy, and 5) direct proportionality between nuclear transcription of the S14 gene and T3 nuclear occupancy. The model faithfully predicted the excursions of the mature mRNA-S14 and its nuclear precursor. Nuclear retention of T3 and the effects of circadian variation on S14 gene transcription explain the apparent prolongation in the t1/2 of decay of mature mRNA. Our findings illustrate the feasibility of incorporating parameters at the molecular level into a comprehensive kinetic analysis of hormone action.
我们在初步实验中发现，每日多次注射三碘甲状腺原氨酸（T3）会导致mRNA-S14衰变的半衰期（t1/2）明显延长。为了恰当地解释这些观察结果，我们建立了一个数学模型，用于描述单次注射或每日多次注射T3后mRNA-S14及其核前体的波动情况。模型参数包括：1）血浆蛋白结合和代谢清除率对受体结合的核T3的影响；2）mRNA-S14的三倍昼夜节律变化；3）核前体的12分钟t1/2和成熟mRNA-S14的1.5小时t1/2；4）先前推导的血浆T3水平与核占有率之间的关系；5）S14基因的核转录与T3核占有率之间的直接比例关系。该模型准确地预测了成熟mRNA-S14及其核前体的波动情况。T3的核滞留以及昼夜节律变化对S14基因转录的影响解释了成熟mRNA衰变t1/2的明显延长。我们的研究结果说明了将分子水平的参数纳入激素作用综合动力学分析的可行性。
