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Hemodynamic regulation of blood-brain barrier phenotype: A cooperative effort linking adherens and tight junction complexes

Walsh, Tony G. (2010) Hemodynamic regulation of blood-brain barrier phenotype: A cooperative effort linking adherens and tight junction complexes. PhD thesis, Dublin City University.

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Abstract

Intercellular adherens junction (AJ) and tight junction (TJ) proteins (e.g. VE-Cadherin, occludin, ZO-1, claudin-5) jointly consolidate the apical surface of adjacent brain microvascular endothelial cells (BBMvEC’s) creating the blood-brain barrier (BBB), a critical regulator of CNS homeostasis. Junctional disassembly and barrier dysfunction are established features of cerebrovascular diseases (e.g. stroke) manifesting compromised blood flow, allowing us to hypothesize a pivotal regulatory link between BBB phenotype and flow-associated shear stress. In this regard, our research has demonstrated that exposure of BBMvEC’s to physiological levels of shear stress in vitro can upregulate tight junction protein expression and enhance protein immunolocalization at the cell-cell border, in parallel with reduced paracellular solute flux. For these studies, cultured bovine brain microvascular endothelial cells (BBMvEC’s) were exposed to laminar shear stress (0-10 dynes/cm 2, 0-24 h) in conjunction with targeted inhibition strategies to delineate the intracellular signaling pathways mediating adaptation of BBB phenotype to fluid shear stress. Initial findings showed that shear-dependent reduction in BBMvEC permeability was initially observed after 3-6 h of shear onset (10 dynes/cm2), with more significant decreases observed after 12 and 24 h. These responses were temporally mirrored by BBMvEC morphological realignment, and were reversed by flow reduction (i.e. to 1 dynes/cm2, 24 h), the latter flow reduction also attenuated the enhanced cell-cell border localization of ZO-1 and reduction in phosphotyrosine (pTyr)-occludin levels induced by high shear.

Item Type:Thesis (PhD)
Date of Award:November 2010
Refereed:No
Supervisor(s):Cummins, Philip
Uncontrolled Keywords:• Blood-Brain Barrier • Occludin • Claudin-5 • ZO-1 • VE-cadherin • Shear Stress
Subjects:Biological Sciences > Cell biology
Medical Sciences > Diseases
Medical Sciences > Biomechanics
Medical Sciences > Physiology
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Biotechnology
DCU Faculties and Schools > Faculty of Science and Health > School of Health and Human Performance
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. View License
Funders:Embark-IRCSET, SFI
ID Code:15703
Deposited On:04 Apr 2011 15:01 by Phil Cummins. Last Modified 20 Sep 2012 04:02

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