Thesis (Ph.D.)--Aberdeen University, 2009. / Title from web page (viewed on June 11, 2009). Includes bibliographical references.

We observed that platelets, which mediate thrombus formation, also enhance fibrinolysis by single-chain urokinase (scuPA).  Preliminary data suggested that this enhancement was due to platelet thrombospondin (TSP), which, depending upon the specifics of the environment, changed conformation, influencing its role in the fibrinolytic system.  Results showed that the activity of scuPA was enhanced by platelets, regardless of platelet treatment or protein release, and that TSP could not explain the platelet effect.  Investigation of the underlying mechanism, using the non-cleavable mutant scuPA (K158E) and protease inhibitors, showed that the platelet-dependent enhancement of scuPA arose from the activation to uPA by a serine protease.  Factor VII activating protease (FSAP) was not the protease responsible, since inhibition of platelet FSAP with function-blocking antibodies did not inhibit the platelet effect.  Comparison of plasminogen and plasma kallikrein, using an array of inhibitors, showed that both candidates mirrored the platelet effect.  Further results, including those from assessment of protease activity on platelets against chromogenic substrates and from the evaluation of uPA formation over time, were consistent with the involvement of plasminogen.  In addition, experiments with platelets from plasminogen-deficient mice showed that platelets lacking plasminogen no longer activated scuPA.  The enhancement of scuPA was found to be platelet-dependent, even in plasma; scuPA activation was more efficient when plasminogen was associated with the platelet membrane, compared to in solution; and the presence of membranes was essential to induce rapid lysis by scuPA.  Our findings indicate that platelets stimulate fibrinolysis by scuPA via local activation to uPA by platelet-associated plasminogen, which is activated by scuPA, consistent with a system of reciprocal activation.

Thesis (M. Phil.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 73-90). Also available in print.

Diss. (sammanfattning) Göteborg : Göteborgs universitet , 2007. / Härtill 4 uppsatser.

published_or_final_version / Pharmacology and Pharmacy / Master / Master of Philosophy

Thesis (doctoral)--Karolinska Institutet, Stockholm, 1991. / T.p. with thesis statement inserted. Includes bibliographical references.

Thesis (doctoral)--Karolinska Institutet, Stockholm, 1991. / T.p. with thesis statement inserted. Includes bibliographical references.

La neuroinflammation est un dénominateur commun de plusieurs troubles du système nerveux central. Les réactions inflammatoires sont souvent médiées par plusieurs voies de signalisation qui conduisent à l'ouverture de la barrière hémato-encéphalique. L'activateur tissulaire du plasminogène (tPA) est une serine protéase qui induit l'ouverture de la barrière hémato-encéphalique. Au cours des dernières années, il a également été montré que les récepteurs NMDA situés dans les cellules endothéliales peuvent jouer un rôle crucial dans la propagation de la réaction inflammatoire.Mon travail au cours de ma thèse a mis l'accent sur la découverte des mécanismes par lesquels le récepteur NMDA effectue une médiation de l'ouverture de la barrière hémato-encéphalique induite par le TPA. Dans notre première étude, nous montrons que les récepteurs NMDA endothéliaux sont des cibles thérapeutiques potentielles pour prévenir l'infiltration et l'inflammation des cellules immunitaires médiées par l'EAE. Nous montrons que l'anticorps monoclonal du récepteur NMDA spécifique à la souris, le Glunomab, pourrait protéger la barrière de la moelle épinière de dommages inflammatoires. Nous montrons également que les récepteurs NMDA sont exprimés en étroite association avec les protéines de jonction serrées dans les cellules endothéliales cérébrales. Dans notre deuxième étude, nous montrons pour la première fois que les récepteurs NMDA neuroendothéliaux peuvent présenter une action métabotropique lors de l'inflammation. Nous soulignons également que ces récepteurs sont en effet des récepteurs NMDA non conventionnels exprimant la sous unité GluN3A. En outre, nous rapportons que le tPA accélère l'ouverture de la barrière hémato-encéphalique en présence d'une agoniste rare de la glycine par un mécanisme dépendant de l'activation de RhoA. Les résultats de mon projet apportent une nouvelle vision du rôle des récepteurs NMDA métabotropiques dans les cellules endothéliales cérébrales. En outre, il fournit également des détails plus précis sur l'ouverture de la barrière hémato-encéphalique via l’activateur tissulaire du plasminogène. / Neuroinflammation is a common denominator of several central nervous system disorders. Inflammatory reactions are often mediated by several signaling pathways which lead to the opening of the blood brain barrier. Tissue plasminogen activator (tPA) is a serine protease induces opening of the blood brain barrier. In recent years, it has also been shown that NMDA receptors located in endothelial cells can play a crucial role in propagation of inflammatory reaction. My doctoral study focused on the finding the underlying mechanisms of action(s) by which NMDA receptor mediates tPA induced opening of the blood brain barrier. In our first study we show that endothelial NMDA receptors are potential therapeutic targets to prevent EAE mediated immune cell infiltration and inflammation. We show that NMDA receptor specific mouse monoclonal antibody Glunomab could prevent the brain spinal cord barrier from inflammatory damage. We also show that NMDA receptors are expressed in close association of tight junction proteins in cerebral endothelial cells. In our second study, we show for the first time that, neuroendothelial NMDA receptors can exhibit metabotropic mode of action during inflammation. We also highlight that these receptors are indeed GluN3A expressing non-conventional NMDA receptors. In addition, we report that tPA accelerates the opening of blood brain barrier in presence of an uncommon agonist glycine by RhoA activation dependent mechanism.My project results provide a nouvelle insight for the role of metabotropic NMDA receptors in cerebral endothelial cells. In addition it also provides more precise details of blood brain barrier opening mediated by tissue plasminogen activator.

Excerpt: The recent study by Sahlas et al1 in the Journal of Stroke and Cerebrovascular Diseases concluded that “the estimation of a patient's weight in the acute setting can lead to overcalculation of the tissue plasminogen activator dose, which is associated with poorer functional outcomes.” However, this conclusion is not well supported by their study1 because the most severe ischemic stroke cases were the ones that were most likely not weighed, and this severity could have led to the increased mortality that was found2 and the majority of unweighed patients were actually given an underdose that was associated with better discharge outcomes, as explained below.

Pang Petti. / "August 2004." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.