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035 a| (Sirsi) o968302096;

035 a| (OCoLC)968302096;

049 a| EREE;

100 1 a| Holt, Andrew W.,e| author.?| UNAUTHORIZED;

245 10 a| Vasodilator-stimulated phosphoprotein regulates arterial smooth muscle cell migration /c| by Andrew W. Holt.;

264 1 a| [Greenville, N.C.] :b| [East Carolina University],c| 2016.;

300 a| 154 pages :b| illustrations (chiefly color).;

336 a| textb| txt2| rdacontent;

337 a| computerb| c2| rdamedia;

338 a| online resourceb| cr2| rdacarrier;

347 a| text fileb| PDFc| 3.61 MB2| rda;

490 1 a| ECU Brody School of Medicine dissertation;

538 a| System requirements: Adobe Reader.;

538 a| Mode of access: World Wide Web.;

502 b| Ph.D.c| East Carolina Universityd| 2016.;

500 a| Presented to the faculty of the Department of Physiology.;

500 a| Advisor: David Tulis.;

500 a| Title from PDF t.p. (viewed January 23, 2017).;

520 3 a| Cardiovascular disease (CVD) is a multi-faceted pathology that remains the number one killer of all Americans and people worldwide. Vascular inflammation, endothelial dysfunction, extracellular matrix imbalance, and arterial smooth muscle (ASM) cell proliferation and migration all contribute to the pathogenesis of occlusive CVD. Important roles for protein kinase signals in controlling aspects of ASM cell migration in the context of CVD are well documented in the scientific literature, and recent findings from our lab and others suggest post-translational modification (PTM) of downstream kinase targets could highlight unique mechanisms and thereby elucidate more precise pharmacotherapeutic targets to combat CVD. In this light, actin-binding vasodilator-stimulated phosphoprotein (VASP) is a critical regulator of adherent cell migration, a readout of protein kinase G (PKG) activity, and a potential attractive candidate for therapeutic intervention. We hypothesized that phosphorylation of VASP on Serine 239 (pVASP.S239) confers the anti-migratory effects of PKG in ASMs. Using in vivo and in vitro models with endogenous and exogenous stimulation of canonical PKG/VASP, we demonstrate the functional ability of this system to attenuate ASM cell migration in the context of CVD. Using site-directed mutagenesis (SDM) and rat cells expressing wild-type VASP, data suggest that pVASP.S239 negates the inhibitory effects of full-length VASP overexpression on cell migration and that this is reversed with a phosphorylation-resistant VASP mutant. Alternate to our hypothesis, these results suggest that pVASP.S239 is not effective in preventing or controlling pathologic ASM cell migration. Importantly however, using SDM along with pharmacologic kinase blockade, data reveal a novel negative feedback loop whereby pVASP.S239 suppresses PKG activity which can be rescued with PKG stimulation. Collectively, using newly developed and advanced techniques for studying cell migration in situ, these findings highlight the importance of VASP and establish the efficacy of PKG in attenuating uncontrolled ASM cell migration independent of pVASP.S239. Clinically, our data demonstrate a potential regulatory element that, with future examination, could lead to potential adjunctive therapies for occlusive vascular diseases involving ASM.;

504 a| Includes bibliographical references.;

650 2 a| Cardiovascular Diseases.=| ^A918029;

650 2 a| Cell Adhesion Molecules.=| ^A933545;

650 2 a| Cell Movement.=| ^A919337;

650 2 a| Microfilament Proteins.=| ^A926004;

650 2 a| Myocytes, Smooth Muscle.=| ^A1326620;

650 2 a| Phosphoproteins.=| ^A1203647;

653 a| PKG;

653 a| VASP;

700 1 a| Tulis, David,e| degree supervisor.=| ^A1366606;

710 2 a| East Carolina University.b| Department of Physiology.?| UNAUTHORIZED;

830 0 a| ECU Brody School of Medicine dissertation.?| UNAUTHORIZED;

856 40 z| Access via ScholarShipu| http://hdl.handle.net/10342/5999;

949 o| wjh;

994 a| C0b| ERE;

096 a| WG 120;

596 a| 1 4;

998 a| 4604910;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 4604910-1001l| JNETm| JOYNERr| Ys| Yt| JNE3ETDu| 1/13/2017x| ETDz| JERESOURCE;

999 a| CLICK ON WEB ADDRESSw| ASISc| 1i| 4604910-2001l| HSLELECm| HSLr| Ys| Yt| HEETDu| 1/13/2017x| ETDz| HERESOURCE;

Vasodilator-stimulated phosphoprotein regulates arterial smooth muscle cell migration / by Andrew W. Holt.

Author/creator	Holt, Andrew W. author.
Other author	Tulis, David, degree supervisor.
Other author	East Carolina University. Department of Physiology.
Format	Theses and dissertations
Publication	[Greenville, N.C.] : [East Carolina University], 2016.
Description	154 pages : illustrations (chiefly color).
Supplemental Content	Access via ScholarShip
Subjects	Cardiovascular Diseases. Cell Adhesion Molecules. Cell Movement. Microfilament Proteins. Myocytes, Smooth Muscle. Phosphoproteins.

Series	ECU Brody School of Medicine dissertation ECU Brody School of Medicine dissertation. UNAUTHORIZED
Summary	Cardiovascular disease (CVD) is a multi-faceted pathology that remains the number one killer of all Americans and people worldwide. Vascular inflammation, endothelial dysfunction, extracellular matrix imbalance, and arterial smooth muscle (ASM) cell proliferation and migration all contribute to the pathogenesis of occlusive CVD. Important roles for protein kinase signals in controlling aspects of ASM cell migration in the context of CVD are well documented in the scientific literature, and recent findings from our lab and others suggest post-translational modification (PTM) of downstream kinase targets could highlight unique mechanisms and thereby elucidate more precise pharmacotherapeutic targets to combat CVD. In this light, actin-binding vasodilator-stimulated phosphoprotein (VASP) is a critical regulator of adherent cell migration, a readout of protein kinase G (PKG) activity, and a potential attractive candidate for therapeutic intervention. We hypothesized that phosphorylation of VASP on Serine 239 (pVASP.S239) confers the anti-migratory effects of PKG in ASMs. Using in vivo and in vitro models with endogenous and exogenous stimulation of canonical PKG/VASP, we demonstrate the functional ability of this system to attenuate ASM cell migration in the context of CVD. Using site-directed mutagenesis (SDM) and rat cells expressing wild-type VASP, data suggest that pVASP.S239 negates the inhibitory effects of full-length VASP overexpression on cell migration and that this is reversed with a phosphorylation-resistant VASP mutant. Alternate to our hypothesis, these results suggest that pVASP.S239 is not effective in preventing or controlling pathologic ASM cell migration. Importantly however, using SDM along with pharmacologic kinase blockade, data reveal a novel negative feedback loop whereby pVASP.S239 suppresses PKG activity which can be rescued with PKG stimulation. Collectively, using newly developed and advanced techniques for studying cell migration in situ, these findings highlight the importance of VASP and establish the efficacy of PKG in attenuating uncontrolled ASM cell migration independent of pVASP.S239. Clinically, our data demonstrate a potential regulatory element that, with future examination, could lead to potential adjunctive therapies for occlusive vascular diseases involving ASM.
General note	Presented to the faculty of the Department of Physiology.
General note	Advisor: David Tulis.
General note	Title from PDF t.p. (viewed January 23, 2017).
Dissertation note	Ph.D. East Carolina University 2016.
Bibliography note	Includes bibliographical references.
Technical details	System requirements: Adobe Reader.
Technical details	Mode of access: World Wide Web.

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Vasodilator-stimulated phosphoprotein regulates arterial smooth muscle cell migration / by Andrew W. Holt.

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