Research Summary
The central focus of the work in Dr. Almon's laboratory is developing mathematical models that describe complex phenomena in biological systems. A central vehicle for this work is the class of anti-inflammatory/immunosuppressive drugs known as corticosteroids. This important class of drugs has severe side effects which include muscle atrophy, osteoporosis, insulin resistant diabetes, arthrosclerosis and, hypertension. These systemic pathologies derive from the combined effect of corticosteroids on many different tissues. Experimentally, we use the drug as a defined input perturbation to populations of animals and use destructive sampling to evaluate the response over time. Associated with the interest in corticosteroids is the study of systems phenomena that relate either to the use of corticosteroids such as arthritis or to the pathologies caused by corticosteroid such as diabetes and muscle wasting. Our approach is to treat all measurements on a population of animals as derived if they were derived from one “giant rat”. We then try to develop quantitative models that explain how gene expression changes in multiple tissues (liver, skeletal muscle, kidney, adipose tissue) cause complex systemic response responses. The intent is to integrate systemic physiological measurements such as blood glucose or lipid profiles with broad changes in gene expression in multiple tissues.
Recent Publications
- Almon, R.R., Yang, E., Lai, W., Androulakis, I.P., DuBois, D.C., and Jusko, W.J. Circadian variations in liver gene expression: relationships to drug actions.Sep;326(3):700-16. Epub 2008 Jun 18. PMID: 18562560 J. Pharmacol. Exp. Therapeutics 2008.
- Almon, R.R., Yang, E., Lai, W., Andoulakis, I.P., Ghimbovschi, S., Hoffman, E.P., Jusko, W.J., and DuBois, D.C. Relationships between circadian rhythms and modulation of gene expression by glucocorticoids in skeletal muscle. Oct;295(4):R1031-47. Epub 2008 Jul 30. PMID: 18667713 Am J. Physiology 2008.
- Earp, J.C., DuBois, D.C., Molano, D.S., Pyszczynski, N.A., Almon, R.R., and Jusko, W.J. Modeling corticosteroid effects in a rat model of rheumatoid arthritis II: Mechanistic pharmacodynamic model for dexamethasone effects in Lewis rats with collagen-induced arthritis. J. Pharmacol. Exp. Therapeutics, 326: 546-554, 2008.
- Earp, J.C., DuBois, D.C., Molano, D.S., Pyszczynski, N.A., Keller, C.E., Almon, R.R., and Jusko, W.J. Modeling corticosteroid effects in a rat model of rheumatoid arthritis I: Mechanistic disease progression model for the time course of collagen-induced arthritis in Lewis rats. J. Pharmacol. Exp. Therapeutics: 326: 532-545, 2008
- Yao, Z., DuBois, D.C.., Almon, R.R., and Jusko, W.J. Pharmacodynamic/ pharmacogenomic modeling of the insulin resistant genes in rat muscle after methylprednisolone treatment: Exploring regulatory signaling cascades. Gene Reg. Sys. Biol., 2: 141-161, 2008.
- Hazra, A., DuBois, D.C., Almon, R.R., Snyder, G.H., and Jusko, W.J. Pharmacodynamic modeling of acute and chronic effects of methylprednisolone on hepatic urea cycle genes in rats. Gene Reg. Sys. Biol., 2: 1-19, 2008.
- Yang, E., Almon, R.R., DuBois, D.C., Jusko, W.J., and Androulakis, I.P. Extracting global System dynamics of corticosteroid genomic effects in rat liver. J. Pharmacol. Exp. Therapeutics. 324: 1243-1254, 2008
- Yao Z, DuBois DC, Almon RR, Jusko WJ. Pharmacokinetic/pharmacodynamic modeling of corticosterone suppression and lymphocytopenia by methylprednisolone in rats. J Pharm Sci. 2008 Jul;97(7):2820-32.
- Hazra A, Pyszczynski NA, DuBois DC, Almon RR, Jusko WJ. Modeling of corticosteroid effects on hepatic low-density lipoprotein receptors and plasma lipid dynamics in rats. Pharm Res. 2008 Apr;25(4):769-80.
- Yao, Z., Hoffman, E.P., Ghimbovschi, S., DuBois, D.C., Almon, R.R., and Jusko, W.J. Mathematical modeling of corticosteroid pharmacogenomics in rat muscle following acute and chronic methylprednisolone dosing. Mol. Pharm., 5: 328-339, 2008.
- Hazra A, Pyszczynski N, DuBois DC, Almon RR, Jusko WJ. Modeling receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase dynamics in rats: dual regulation by endogenous and exogenous corticosteroids. J Pharmacokinet Pharmacodyn.: 34(5):643-67, 2007
- Hazra A, Pyszczynski N, DuBois DC, Almon RR, Jusko WJ. Pharmacokinetics of methylprednisolone after intravenous and intramuscular administration in rats. Biopharm Drug Dispos: 28(6):263-73, 2007
- Almon RR, DuBois DC, Yao Z, Hoffman EP, Ghimbovschi S, Jusko WJ. Microarray analysis of the temporal response of skeletal muscle to methylprednisolone: comparative analysis of two dosing regimens. Physiol Genomics. 30(3):282-99, 2007
- Yang E, Simcha D, Almon RR, Dubois DC, Jusko WJ, Androulakis IP. Context specific transcription factor prediction. Ann Biomed Eng. 35(6):1053-67, 2007
- Androulakis IP, Yang E, Almon RR. Analysis of time-series gene expression data: methods, challenges, and opportunities. Annu Rev Biomed Eng. 9:205-28, 2007
- Yao Z, Zhao B, Hoffman EP, Ghimbovschi S, DuBois DC, Almon RR, Jusko WJ. Application of scaling factors in simultaneous modeling of microarray data from diverse chips. Pharm Res. 24(4):643-9, 2007
- Almon RR, DuBois DC, Jusko WJ. A microarray analysis of the temporal response of liver to methylprednisolone: a comparative analysis of two dosing regimens. Endocrinology. 148(5):2209-25, 2007
- Hazra A, DuBois DC, Almon RR, Jusko WJ. Assessing the dynamics of nuclear glucocorticoid-receptor complex: adding flexibility to gene expression modeling. J Pharmacokinet Pharmacodyn. 34(3):333-54, 2007
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