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Dynamic pharmacodynamic modeling foc...

Lee, Jee Eun.

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Dynamic pharmacodynamic modeling focused on the protein kinase A signaling pathway.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Dynamic pharmacodynamic modeling focused on the protein kinase A signaling pathway./
Author:	Lee, Jee Eun.
Description:	192 p.
Notes:	Adviser: Ronald A. Siegel.
Contained By:	Dissertation Abstracts International68-12B.
Subject:	Engineering, Biomedical. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3291504
ISBN:	9780549369509

Dynamic pharmacodynamic modeling focused on the protein kinase A signaling pathway.
Lee, Jee Eun.

Dynamic pharmacodynamic modeling focused on the protein kinase A signaling pathway. - 192 p.

Adviser: Ronald A. Siegel.

Thesis (Ph.D.)--University of Minnesota, 2008.

A simple mechanism-based pharmacodynamic (PD) model focused on the protein kinase A (PKA) pathway has been conceived in an attempt to understand covariates associated with PD variability. In this model, one possible physiological mechanism underlying variabilities in the apparent Hill coefficient variability is postulated. Variabilities in the levels of effector signaling molecules, whose activation and inactivation processes are governed by the interplay of kinases and phosphatases, may lead to variability in the Hill coefficient.

ISBN: 9780549369509Subjects--Topical Terms:

1017684
Engineering, Biomedical.

Dynamic pharmacodynamic modeling focused on the protein kinase A signaling pathway.
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020 $a 9780549369509
035 $a (UMI)AAI3291504
035 $a AAI3291504
040 $a UMI $c UMI
100 1 $a Lee, Jee Eun. $3 1281009
245 1 0 $a Dynamic pharmacodynamic modeling focused on the protein kinase A signaling pathway.
300 $a 192 p.
500 $a Adviser: Ronald A. Siegel.
500 $a Source: Dissertation Abstracts International, Volume: 68-12, Section: B, page: 7951.
502 $a Thesis (Ph.D.)--University of Minnesota, 2008.
520 $a A simple mechanism-based pharmacodynamic (PD) model focused on the protein kinase A (PKA) pathway has been conceived in an attempt to understand covariates associated with PD variability. In this model, one possible physiological mechanism underlying variabilities in the apparent Hill coefficient variability is postulated. Variabilities in the levels of effector signaling molecules, whose activation and inactivation processes are governed by the interplay of kinases and phosphatases, may lead to variability in the Hill coefficient.
520 $a Methods. Simulations. A simple mathematical model describing the PKA pathway, with kinase and phosphatase counterpoint, regulating the phosphorylation state (phospho-state) of an effector molecule, was studied. Dose response profiles under different cellular conditions were simulated using MatlabRTM, and parameters of the traditional Emax model (Hill coefficients, Emax and EC50) were matched to the simulated dose response curves. An auxiliary model of drug tolerance, in which steadily expressed effector is degraded at different rates depending on its phospho-state, was also investigated, and predictions are made regarding tolerance effects on drug efficacy, potency, and sensitivity.
520 $a Experimental methods. Activated PKA is known to migrate to various regions of the cell and phosphorylates numerous cellular components, including the cAMP response element binding (CREB) protein in the nucleus, which in turn acts as a transcription factor, turning on genes coding for diverse proteins. To investigate the effect of overall level of CREB on the Hill coefficient of the drug response curve (conversion of CREB to pCREB) for the model drug forskolin (a direct stimulator of adenylyl cyclase) was measured. CREB plasmids were transfected into both Human Embryonic Kidney and Madin-Darby Canine Kidney cells. Levels of pCREB were measured using three different assays: immunofluorescence, immunoblotting and cellular enzyme-linked immunosorbent assay.
520 $a Results and conclusions. Simulations showed that the level of effector signaling molecules influenced significantly on Hill coefficient of phosphorylation of effector. Although parameter estimation was not feasible with the data obtained from experiments, likelihood of the effect of CREB on Hill coefficient of phosphorylation of CREB was observed, rendering a leeway for future studies.
590 $a School code: 0130.
650 4 $a Engineering, Biomedical. $3 1017684
650 4 $a Health Sciences, Pharmacology. $3 1017717
690 $a 0419
690 $a 0541
710 2 $a University of Minnesota. $b Pharmaceutics. $3 1058963
773 0 $t Dissertation Abstracts International $g 68-12B.
790 $a 0130
790 1 0 $a Elmquist, William F. $e committee member
790 1 0 $a Fairbanks, Carolyn A. $e committee member
790 1 0 $a Sawchuk, Ronald J. $e committee member
790 1 0 $a Siegel, Ronald A., $e advisor
790 1 0 $a Stone, Laura L. $e committee member
791 $a Ph.D.
792 $a 2008
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3291504