Major mechanisms determining receptor occupancy, expression of various genes, and alterations of several physiological systems will be studied and improved mathematical models for the in vivo pharmacokinetics, pharmacodynamics, and pharmacogenomics (PK/PD/PG) of corticosteroids will be sought. These important agents exert hormonal, immunosuppressive, and diverse biochemical effects by diffusion into cells, binding to cytosolic receptors, and increasing or decreasing turnover of mRNA and gene-mediated synthesis of diverse effector proteins or enzymes. Several systems will be examined with mechanistic, integrated, and comprehensive studies in shared animals given acute and chronic steroid doses.
Aim 1 will extend our current 5th-generation PK/PD/PG model for methylprednisolone (MP) effects on expression of select genes and on microarray-captured multiple genes in 3 tissues (liver, muscle, kidney) of adrenalectomized rats to consider the role of corticosterone (CST), circadian factors, and MP/CST interactions in normal rats.
Aim 2 focuses on diabetogenic effects of steroids including the critical enzyme PEPCK and systemic effects on glucose and insulin in normal and diabetic rats.
Aim 3 evaluates two inter-related adverse effects of steroids on muscle physiology (insulin resistance and atrophy) through expression of IRS-1, myostatin, and glutamine synthase.
Aim 4 assesses expression of select genes and lipid biomarkers accounting for steroid disruption of lipid biochemistry.
Aim 5 expands current efforts using high throughput gene arrays to develop bioinformatic and modeling tools to assess relationships underlying polygenic multi-tissue effects of steroids.
Aim 6 evolves several avenues of improved PK/PD/PG models that account for major mechanisms and processes controlling steroid actions with advancement of systems biological concepts. We will elucidate the pharmacologic basis of several interrelated systemic steroid effects and continue generation of important mechanistic PK/PD/PG concepts and models of drug action.
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