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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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No Study Section (in-house review) (NSS)
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Okita, Richard T
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State University of New York at Buffalo
Schools of Pharmacy
United States
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Rao, Rohit T; Scherholz, Megerle L; Androulakis, Ioannis P (2018) Modeling the influence of chronopharmacological administration of synthetic glucocorticoids on the hypothalamic-pituitary-adrenal axis. Chronobiol Int 35:1619-1636
Zhu, Xu; Trueman, Sheryl; Straubinger, Robert M et al. (2018) Physiologically-based pharmacokinetic and pharmacodynamic models for gemcitabine and birinapant in pancreatic cancer xenografts. J Pharmacokinet Pharmacodyn 45:733-746
Ayyar, Vivaswath S; Sukumaran, Siddharth; DuBois, Debra C et al. (2018) Receptor/gene/protein-mediated signaling connects methylprednisolone exposure to metabolic and immune-related pharmacodynamic actions in liver. J Pharmacokinet Pharmacodyn 45:557-575
Ayyar, Vivaswath S; Sukumaran, Siddharth; DuBois, Debra C et al. (2018) Modeling Corticosteroid Pharmacogenomics and Proteomics in Rat Liver. J Pharmacol Exp Ther 367:168-183
Zhu, Xu; Shen, Xiaomeng; Qu, Jun et al. (2018) Proteomic Analysis of Combined Gemcitabine and Birinapant in Pancreatic Cancer Cells. Front Pharmacol 9:84
Pierre, Kamau; Rao, Rohit T; Hartmanshenn, Clara et al. (2018) Modeling the Influence of Seasonal Differences in the HPA Axis on Synchronization of the Circadian Clock and Cell Cycle. Endocrinology 159:1808-1826
Rao, Rohit T; Androulakis, Ioannis P (2017) Modeling the Sex Differences and Interindividual Variability in the Activity of the Hypothalamic-Pituitary-Adrenal Axis. Endocrinology 158:4017-4037
Rao, Rohit T; Scherholz, Megerle L; Hartmanshenn, Clara et al. (2017) On the analysis of complex biological supply chains: From Process Systems Engineering to Quantitative Systems Pharmacology. Comput Chem Eng 107:100-110
Ayyar, Vivaswath S; DuBois, Debra C; Almon, Richard R et al. (2017) Mechanistic Multi-Tissue Modeling of Glucocorticoid-Induced Leucine Zipper Regulation: Integrating Circadian Gene Expression with Receptor-Mediated Corticosteroid Pharmacodynamics. J Pharmacol Exp Ther 363:45-57
Li, Xiaonan; DuBois, Debra C; Almon, Richard R et al. (2017) Effect of Disease-Related Changes in Plasma Albumin on the Pharmacokinetics of Naproxen in Male and Female Arthritic Rats. Drug Metab Dispos 45:476-483

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