Corticosteroid Pharmacokinetics and Pharmacodynamics

 描述(申请人提供)：该项目旨在提高对皮质类固醇(CS)对基因组和生理过程的影响的药代动力学和机制的了解，这些过程与从局部到全身水平的内分泌、代谢和药理学反应有关。我们的持续研究将扩大我们的机械性评估，以解决有关重要性别差异的知识差距。我们还寻求继续开发药代动力学、药效学、药物基因组学(PK/PD/PG)和疾病(DIS)模型，以揭示生物组织(系统生物学)不同水平的“生物学规则”，并改进体内药物效应的量化和预测。我们的实验范式通常是在特定条件或药物治疗下的动物群体中进行的大型精心控制的研究(“巨鼠”研究)。雄性大鼠的血液和主要器官在一段时间内被采集，反映了内源性生物节律和/或由于单次给药或长期接触CS而造成的体内平衡紊乱的开始和恢复。我们将扩展对较长生物节律(发情周期)中短节律(昼夜节律)相互作用的计算和建模，进一步研究类固醇作用中的性别差异，并进化出更多与生理相关的小系统到广泛系统的药理学模型。具体目标1将通过扩展我们的核心实验范式来阐明昼夜节律中的性别差异，以提供作为发情阶段函数的正常周期雌性大鼠不同基因和生物标记物的精心制定的基线(昼夜节律/发情周期)曲线。特定目标2将评估单次剂量的原型CS，甲基强的松龙，作为周期阶段的功能完整的雌性大鼠的PK/PD，以检查糖尿病的葡萄糖/胰岛素/脂联素/脂肪酸系统和骨转换系统的性别决定因素。具体目标3将我们以前在雄性大鼠身上使用的胶原蛋白诱导的关节炎模型扩展到雌性大鼠。我们将从炎症和骨骼动力学过程的基本数学模型发展到复杂的数学模型，以解释性别差异，将这些新的测量与我们来自正常和关节炎雄性大鼠的广泛数据文件相结合。特定目标4将使用和发展“自上而下”的计算方法来评估血液和组织中的基因、蛋白质和生物标记物的昼夜节律和对CS的全球响应，以揭示雄性动物与雌性动物之间潜在的间接调节机制。这些整体研究和数学模型创新将改进对性别差异高度相关的关键生物功能的多尺度理解，并将在定量药理学中得到广泛应用。

 DESCRIPTION (provided by applicant): This project seeks to provide increased understanding of pharmacokinetics and mechanisms of corticosteroid (CS) effects on genomic and physiologic processes associated with endocrinologic, metabolic, and pharmacologic responses from local to systemic levels for CS dosed acutely and chronically. Our continued research will expand our mechanistic assessments to address gaps in knowledge about important sex differences. We also seek to continue development of pharmacokinetic, pharmacodynamic, pharmacogenomic (PK/PD/PG) and Disease (DIS) models that reveal the `rules of biology' at various levels of biological organization (systems biology) and allow improved quantitation and prediction of in vivo drug effects. Our experimental paradigm has often been large carefully-controlled studies in groups of animals subjected to defined conditions or drug treatments ("giant rat" studies). Blood and major organs of male rats were harvested over time frames reflecting either endogenous biorhythms and/or the onset and recovery of changes produced by single-doses or prolonged disturbances of homeostasis produced by chronic exposures of CS. We will expand computations and modeling for the interaction of a short rhythm (circadian) within a longer biorhythm (estrous cycle), further examine sex differences in steroid actions, and evolve more physiologically-relevant small to extensive systems pharmacologic models. Specific Aim 1 will elucidate sex differences in circadian rhythms by extending our core experimental paradigm to provide carefully-enacted baseline (circadian/estrous cycle) profiles of diverse genes and biomarkers in normal cycling female rats as a function of estrous stage. Specific Aim 2 will assess the PK/PD of single doses of a prototypic CS, methylprednisolone, in cycling intact female rats as a function of cycle stage to examine sex determinants of the diabetogenic glucose/insulin/adiponectin/fatty acid system and bone turnover systems. Specific Aim 3 will extend our previous use of the collagen-induced arthritis model in male rats to females. We will evolve basic to complex mathematical models for inflammatory and bone dynamic processes to account for sex differences, combining these new measurements with our extensive data files from normal and arthritic male rats. Specific Aim 4 will employ and evolve "top-down" computational approaches to assess circadian rhythms and global responsiveness to CS of genes, proteins, and biomarkers in blood and tissues to reveal potential indirect regulatory mechanisms in male versus female animals. These holistic studies and mathematical modeling innovations will provide improved multi-scale understanding of critical biological functions where sex differences are highly relevant and will have wide applications in quantitative pharmacology.