Our work has been the first to demonstrate the brain's intrinsic capacity to regulate expression of hemostasis factors. Given the overwhelming importance of thromboembolic occlusion in stroke, defining molecular mechanisms of brain-specific hemostasis is a critical issue. Recent advances in genetics of ischemic stroke have emphasized the role of the phospodiesterase-4 (PDE4) enzymatic pathway. Initial work has demonstrated that low expression of PDE4D isoforms are associated with increased risk for both carotid and cardiogenic stroke. For the current project, we will focus on regulation of brain fibrinolysis via the PDE4 pathway, and its relationship with ischemic stroke. Our preliminary data show a) substantial linkage between PDE4D and tissue plasminogen activator expression, and b) increased infarct size with PDE4 inhibition. We have previously demonstrated an important role for brain pericytes in regulating expression of tPA and the serpin protease nexin-1 (PN-1). We propose to define the role of PDE4 as regulator and mediator of pericye and astrocyte effects on endothelial fibrinolysis. We will incorporate an in vitro model of ischemia, oxygen-glucose deprivation, to fully analyze these effects. Moreover, given the increasing recognition of inflammation in pathogenesis of ischemic stroke, we will study endotoxin effects on brain microvascular fibrinolysis. Specifically, we will define how PDE4 may mediate pericyte-dependent brain microvascular endothelial hyper-responsiveness to endotxoin. We will also analyze the in vivo role of PDE4 and PDE4D in the brain microvascular response to endotoxin, using rats pretreated with rolipram and mice null for PDE4D. We will define the role of PDE4 as regulator of both blood-brain barrier formation as well as brain microvascular fibrinolysis, conducting both in vitro and in vivo studies. Finally, we will analyze the role of PDE4 and PDE4D expression in mouse and rat experimental stroke models, and define the role of fibrinolysis as mediator between PDE4/PDE4D expression and infarct size in experimental stroke models. PDE4 thus represents a potentially critical enzymatic link between fibrinolysis, the blood-brain barrier, and ischemic stroke. We are also prepared to investigate, as necessary, other cAMP-mediated pathways, and non-cAMP-mediated pathways, regulating fibrinolysis, inflammation, and blood brain barrier formation. Completion of these studies will provide new insights for the molecular mechanisms regulating brain microvascular fibrinolysis, allowing for development of new strategies to prevent and treat stroke by modification of brain microvascular hemostasis function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS020989-23
Application #
7795722
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Jacobs, Tom P
Project Start
1984-07-01
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
23
Fiscal Year
2010
Total Cost
$330,259
Indirect Cost
Name
University of California Irvine
Department
Neurology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Lo, Patrick; Crouzet, Christian; Vasilevko, Vitaly et al. (2016) Corrigendum to ""Visualization of microbleeds with optical histology in mouse model of cerebral amyloid angiopathy"" [105, May 2016, 109-113]. Microvasc Res 106:137
Passos, Giselle F; Kilday, Kelley; Gillen, Daniel L et al. (2016) Experimental hypertension increases spontaneous intracerebral hemorrhages in a mouse model of cerebral amyloidosis. J Cereb Blood Flow Metab 36:399-404
Lo, Patrick; Crouzet, Christian; Vasilevko, Vitaly et al. (2016) Visualization of microbleeds with optical histology in mouse model of cerebral amyloid angiopathy. Microvasc Res 105:109-13
Fisher, Mark; Moores, Lisa; Alsharif, Mohamad N et al. (2016) Definition and Implications of the Preventable Stroke. JAMA Neurol 73:186-9
Li, Lin; Fisher, Mark; Lau, Wei-Ling et al. (2015) Cerebral microbleeds and cognitive decline in a hemodialysis patient: Case report and review of literature. Hemodial Int 19:E1-7
Wong, Jonathan M; Lombardo, Dawn; Handwerker, Jason et al. (2014) Cryptogenic stroke and the left atrial septal pouch: a case report. J Stroke Cerebrovasc Dis 23:564-5
Liu, Shuo; Grigoryan, Mher Mahoney; Vasilevko, Vitaly et al. (2014) Comparative analysis of H&E and Prussian blue staining in a mouse model of cerebral microbleeds. J Histochem Cytochem 62:767-73
Fisher, Mark (2014) Cerebral microbleeds: where are we now? Neurology 83:1304-5
Yang, Fan; Sumbria, Rachita K; Xue, Dong et al. (2014) Effects of PDE4 pathway inhibition in rat experimental stroke. J Pharm Pharm Sci 17:362-70
Fisher, Mark (2013) MRI screening for chronic anticoagulation in atrial fibrillation. Front Neurol 4:137

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