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1. Manne, Bhanu Kanth. CLEC-2 SIGNAL TRANSDUCTION IN PLATELET ACTIVATION.
Degree: PhD, 2015, Temple University
Platelets are involved in many processes ranging from fighting microbial infections and triggering inflammation to promoting tumor angiogenesis and metastasis. Nevertheless, the primary physiological function of platelets is to act as essential mediators in maintaining homeostasis of the circulatory system by forming hemostatic thrombi that prevent blood loss and maintain vascular integrity. CLEC-2 is a C-type lectin-like receptor that is highly expressed in platelets and lesser extent, in other cell types such as activated dendritic cells and B cells. Rhodocytin was the first ligand used to identify CLEC-2 receptor and it’s signaling on platelets. In the first chapter we identified a new agonist for CLEC-2 receptor. Fucoidan, a sulfated polysaccharide from fucus vesiculosus, decreases bleeding time and clotting time in hemophilia, possibly through inhibition of tissue factor pathway inhibitor. However, its effect on platelets and the receptor by which fucoidan induces cellular processes has not been elucidated. In this study, we demonstrate that fucoidan induces platelet activation in a concentration-dependent manner. Fucoidan-induced platelet activation was completely abolished by the pan-Src family kinase (SFK) inhibitor, PP2, or when Syk is inhibited. PP2 abolished phosphorylation of Syk and Phospholipase Cγ−2. Fucoidan-induced platelet activation had a lag phase, which is reminiscent of platelet activation by collagen and CLEC-2 receptor agonists. Platelet activation by fucoidan was only slightly inhibited in FcRγ chain null mice, indicating that fucoidan was not acting primarily through GPVI receptor. On the other hand, fucoidan-induced platelet activation was inhibited in platelet-specific CLEC-2 knock-out murine platelets revealing CLEC-2 as a physiological target of fucoidan. Thus, our data show fucoidan as a novel CLEC-2 receptor agonist that activates platelets through a SFK-dependent signaling pathway. Furthermore, the efficacy of fucoidan in hemophilia raises the possibility that decreased bleeding times could be achieved through activation of platelets. Lipid rafts are distinct areas of the plasma membrane implicated in the regulation of signaling in a variety of cells including platelets. A previous study C-type lectin like receptor 2 (CLEC-2) has been reported to activate platelets through a lipid raft-dependent manner. Secreted ADP potentiates CLEC-2-mediated platelet aggregation. We have investigated whether the decrease in CLEC-2-mediated platelet aggregation, previously reported in platelets with disrupted rafts, is a result of the loss of agonist potentiation by ADP. We disrupted platelet lipid rafts with methyl-β-cyclodextrin (MβCD) and measured signaling events downstream of CLEC-2 activation. Lipid raft disruption decreases platelet aggregation induced by CLEC-2 agonists. The inhibition of platelet aggregation by the disruption of lipid rafts was rescued by the exogenous addition of epinephrine but not 2-methylthioadenosine diphosphate (2MeSADP), which suggests that lipid raft…Advisors/Committee Members: Kunapuli, Satya P.;, Sabri, Abdelkarim, Scalia, Rosario, Eguchi, Saturo, Tsygankov, Alexander, McKenzie, Steven;.
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APA (6th Edition):
Manne, B. K. (2015). CLEC-2 SIGNAL TRANSDUCTION IN PLATELET ACTIVATION. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,340495
Chicago Manual of Style (16th Edition):
Manne, Bhanu Kanth. “CLEC-2 SIGNAL TRANSDUCTION IN PLATELET ACTIVATION.” 2015. Doctoral Dissertation, Temple University. Accessed August 11, 2020. http://digital.library.temple.edu/u?/p245801coll10,340495.
MLA Handbook (7th Edition):
Manne, Bhanu Kanth. “CLEC-2 SIGNAL TRANSDUCTION IN PLATELET ACTIVATION.” 2015. Web. 11 Aug 2020.
Manne BK. CLEC-2 SIGNAL TRANSDUCTION IN PLATELET ACTIVATION. [Internet] [Doctoral dissertation]. Temple University; 2015. [cited 2020 Aug 11]. Available from: http://digital.library.temple.edu/u?/p245801coll10,340495.
Council of Science Editors:
Manne BK. CLEC-2 SIGNAL TRANSDUCTION IN PLATELET ACTIVATION. [Doctoral Dissertation]. Temple University; 2015. Available from: http://digital.library.temple.edu/u?/p245801coll10,340495