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.
This project will extend the pursuit of carefully-controlled, detailed studies of endogenous biorhythms and pharmacologic responses to corticosteroids in blood and tissues comparing male and female rats. Situations where gaps exist in understanding about sex differences such as diabetes, inflammation, and bone turnover will be examined. The experimental studies are complemented by the development of advanced methodology and mathematical models that reveal and quantitate 'the rules of biology and pharmacology' relevant to diverse drugs in addition to corticosteroids.
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