This project provides increased understanding of mechanisms of corticosteroid effects on genomic and physiologic processes associated with endocrinologic, metabolic, pharmacologic, and toxicologic responses to agents given acutely and chronically. We will continue developing pharmacokinetic-pharmacodynamic- pharmacogenomic-disease (PK/PD/PG/Dis) models which reveal the'rules of biology'at various levels of biological organization (systems biology) and allow improved quantitation and prediction of in vivo drug effects.
Specific aims i nclude: 1.) Assessing circadian patterns of gene expression. Our studies in liver and muscle reveal diverse clusters of genes with circadian patterns that peak at various times of the day. Adding more tissues and cross-tissue comparisons will provide a mechanistic rationale for multi-organ harmonies in circadian rh3/thms. 2.) Role of circadian dosing of therapeutic steroids. Models coupled to circadian rh3rthms will simulate and test methods of selecting optimal doses and time-of-day for therapy with corticosteroids. 3.) Corticosteroid control of diabetogenic effects. Diverse genes and biomarkers will serve to evolve multi-organ systems biology models for steroid control of glucose metabolism. 4.) Assess anti-inflammatory effects of corticosteroids. Our small systems model accounting for the role of inflammatory cjrtokines in causing rat paw edema and bone erosion will be expanded. 5.) Extend bioinformatic assessment of corticosteroid pharmacogenomics. Improved computational techniques will allow cross-tissue comparisons of genes affected, acute versus chronic drug effects, and baseline versus circadian-dose drug effects. The steroids regulate diverse metabolic systems and growing database offers a unique opportunity for assessment and functional integration. 6.) Develop companion LC/MS/MS methodology to jointly assess both genomic and proteomic effects of corticosteroids. 7.) Improved PK/PD/PG/Disease models. We have an extensive relational data base tracking each biomarker, tissue, animal, time, dose, and experiment. Our previous and planned studies compliment each other. These measurements will be integrated and used with increasingly advanced systems models to quantitate and explain corticosteroid effects at molecular, cellular, organ, and whole body levels of biological organization in normal and selected disease conditions.
Glucocorticoids are essential hormones controlling diverse metabolic functions. They are potent agents when used therapeutically as corticosteroids, but numerous severe adverse effects limit their clinical use. We seek improved understanding of endogenous and pharmacologic factors controlling gene expression in various tissues including circadian rhythms and will develop improved mathematical models to capture multiple factors controlling anti-inflammatory effects and disturbances of various metabolic systems.
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