Department of Biomedical Engineering, Rutgers University, Piscataway, NJ 08854, USA.
IEEE Trans Biomed Eng. 2011 Dec;58(12):3504-7. doi: 10.1109/TBME.2011.2162236. Epub 2011 Jul 18.
Glucocorticoids are steroid hormones which, among other functions, exert an antiinflammatory effect. Endogenous glucocorticoids are normally secreted by the adrenal gland in discrete bursts. It is becoming increasingly evident that this pulsatile secretion pattern, leading to ultradian rhythms of plasma glucocorticoid levels, may have important downstream regulatory effects on glucocorticoid-responsive genes. Mathematical modeling of this system can compliment recent experimental data and quantitatively evaluate hypothesized mechanistic underpinnings of differential pulsatile signal transduction. In this paper, we describe an integrated model of pulsatile secretion of glucocorticoids by the hypothalamic-pituitary-adrenal (HPA) axis and the pharmacodynamic effect of glucocorticoids. This model is used to investigate the difference in transcriptional responses to pulsatile and constant glucocorticoid exposure. Nonlinearity in ligand-receptor kinetics leads to the differential expression of glucocorticoid-responsive genes in response to different patterns of glucocorticoid secretion, even when the total amount of glucocorticoid exposure is held constant. Understanding the implications of ultradian rhythms in glucocorticoids is important in studying the dysregulation of HPA axis function leading to altered glucocorticoid secretion patterns in disease.
糖皮质激素是甾体激素的一种，具有抗炎等多种功能。内源性糖皮质激素通常由肾上腺间断性爆发式分泌。越来越多的证据表明，这种脉冲式分泌模式会导致糖皮质激素水平出现超短周期节律，可能对糖皮质激素反应基因产生重要的下游调节作用。该系统的数学模型可以补充最近的实验数据，并定量评估脉冲式信号转导的假设机制基础。本文描述了一个下丘脑-垂体-肾上腺（HPA）轴脉冲式分泌糖皮质激素和糖皮质激素药效学的综合模型。该模型用于研究脉冲式和持续糖皮质激素暴露的转录反应差异。配体-受体动力学的非线性导致糖皮质激素反应基因的差异表达，即使当糖皮质激素暴露总量保持不变时也是如此。了解糖皮质激素超短周期节律的影响对于研究 HPA 轴功能失调导致疾病时糖皮质激素分泌模式改变非常重要。
