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You searched for +publisher:"Temple University" +contributor:("Woulfe, Donna"). Showing records 1 – 2 of 2 total matches.

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Temple University

1. Bhavaraju, Kamala. MOLECULAR PHYSIOLOGY OF THROMBOXANE A2 GENERATION IN PLATELETS.

Degree: PhD, 2010, Temple University

Molecular and Cellular Physiology

Cardiovascular diseases are a major cause of mortality and morbidity in the developed countries. Anti-platelet therapy is a cornerstone treatment for patients with cardiovascular diseases. Patients are routinely managed with a combination therapy consisting of aspirin and clopidogrel. Aspirin inhibits cyclooxygenase 1 (COX 1) a crucial intermediate enzyme involved in thromboxane biosynthesis. Clopidogrel on the other hand antagonizes ADP receptor P2Y12. ADP is a weak platelet agonist stored in platelet dense granules and is released upon platelet activation. ADP activates platelets through two purinergic receptors namely P2Y1 and P2Y12 these receptors couple to Gq and Gi class of G-proteins, respectively. P2Y1 causes calcium mobilization through activation of PLC-β. P2Y12 inhibits adenylyl cyclase, causes activation of Rap1B and Akt. Signaling from both the receptors is required for complete integrin activation, thromboxane generation and Erk activation. Previous studies have shown that P2Y12 potentiates fibrinogen receptor activation, secretion, thrombi stabilization, thrombin generation, platelet leukocyte aggregation formation. ThromboxaneA2 (TXA2) is a potent platelet agonist generated through arachidonic acid metabolism in platelets. TXA2 thus, generated after platelet activation acts as a positive feedback mediator along with ADP. Under physiological conditions, platelet activation leads to thrombin generation through coagulation cascades. Generated thrombin activates PAR receptors and ADP is released from dense granules, which further potentiates thromboxane generation downstream of PARs. Current anti-platelet therapy regimens often include P2Y12 antagonists and aspirin in management of patients with acute coronary syndrome (ACS) and in those undergoing percutaneous coronary intervention (PCI) with stent implantation. However, there still exists a need for improved treatment strategies as not all patients benefit from this dual combination therapy. Reasons include, poor responders either to P2Y12 antagonists or to aspirin, or if aspirin is contraindicated in these patient populations. In the current study we evaluated the role of P2Y12 in thromboxane generation under physiological conditions. We studied serum thromboxane generation in a model system wherein P2Y12 was antagonized or deficient. Using pharmacological approaches we show that dosing mice with 30mg/Kg/body weight clopidogrel or 3mg/Kg/body weight prasugrel decreased serum thromboxane levels when compared to the control mice. Pre-treatment of human blood ex vivo with active metabolites of clopidogrel (R361015) or prasugrel (R138727) also led to reduction in thromboxane levels. We also evaluated serum thromboxane levels in P2Y receptor null mice, serum thromboxane levels in P2Y1 null mice were similar to those in wild type littermates, and were inhibited in P2Y12 null mice. Furthermore, serum thromboxane levels in P2Y12 deficient patients, previously described in France and Japan, were also evaluated and these…

Advisors/Committee Members: Kunapuli, Satya P., Driska, Steven Paul, Eguchi, Satoru, Woulfe, Donna.

Subjects/Keywords: Biology, Physiology; ADP Receptors; Anti-platelet Therapy; G12/13 Pathways; Platelets; Serum Thromboxane; Thrombin

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Bhavaraju, K. (2010). MOLECULAR PHYSIOLOGY OF THROMBOXANE A2 GENERATION IN PLATELETS. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,92746

Chicago Manual of Style (16th Edition):

Bhavaraju, Kamala. “MOLECULAR PHYSIOLOGY OF THROMBOXANE A2 GENERATION IN PLATELETS.” 2010. Doctoral Dissertation, Temple University. Accessed October 22, 2020. http://digital.library.temple.edu/u?/p245801coll10,92746.

MLA Handbook (7th Edition):

Bhavaraju, Kamala. “MOLECULAR PHYSIOLOGY OF THROMBOXANE A2 GENERATION IN PLATELETS.” 2010. Web. 22 Oct 2020.

Vancouver:

Bhavaraju K. MOLECULAR PHYSIOLOGY OF THROMBOXANE A2 GENERATION IN PLATELETS. [Internet] [Doctoral dissertation]. Temple University; 2010. [cited 2020 Oct 22]. Available from: http://digital.library.temple.edu/u?/p245801coll10,92746.

Council of Science Editors:

Bhavaraju K. MOLECULAR PHYSIOLOGY OF THROMBOXANE A2 GENERATION IN PLATELETS. [Doctoral Dissertation]. Temple University; 2010. Available from: http://digital.library.temple.edu/u?/p245801coll10,92746


Temple University

2. Mao, Yingying. ROLE OF PROTEASE-ACTIVATED RECEPTORS IN PLATELET ACTIVATION.

Degree: PhD, 2009, Temple University

Physiology

Platelets act as a fundamental component of the hemostatic process and their activation leads to the formation of a stable clot at the injured endothelium surface. Thrombin, as the important physiological agonist, activates platelets through protease-activated receptors (PARs). Protease-activated receptors are one of the major receptors in platelets and belong to the seven-transmembrane G-protein couple receptor family. Four protease-activated receptors are found, named as PAR1, PAR2, PAR3 and PAR4. Human platelets express PAR1 and PAR4 and murine platelets express PAR4 and PAR3 instead of PAR1. Thrombin activates PARs through a unique mechanism, involving the cleavage of N-terminus of PAR receptors and the newly exposed N-terminus acts as its own tethered ligand to bind and activate the receptor. In this study, we characterized a new PAR1 specific activating peptide (TFRRRLSRATR), generated from the c-terminus of human platelet P2Y1 receptor, and evaluated its biological function. This peptide activated platelets in a concentration-dependent manner, causing shape change, aggregation, secretion and calcium mobilization. Its activation is completely inhibited by using BMS200261, a PAR-1 specific antagonist. Its specificity to PAR1 receptor is further confirmed by using TFRRR-peptide-pretreated washed platelets and murine platelets. The shape change induced by 10 microM peptide was totally abolished by Y-27632, an inhibitor of p160ROCK which is the downstream signal of G12/13 pathways. The TFRRR-peptide, YFLLRNP, and the physiological agonist thrombin selectively activated G12/13 pathways at low concentrations and began to activate both Gq and G12/13 pathways with increased concentrations. Similar to SFLLRN, the TFRRR-peptide caused phosphorylation of Akt and Erk in a P2Y12 receptor-dependent manner, and p-38 MAP kinase activation in a P2Y12-independent manner. The effects of this peptide are elicited by the first six amino acids (TFRRRL) whereas the remaining peptide (LSRATR), TFERRN, or TFEERN had no effects on platelets. Beside thrombin, PARs also can be activated by other proteases. Previous studies in our lab show that plasmin, a major extracellular protease, activates both human and murine platelets through prototypical cleavage of PAR4 (Quinton et al., 2004). In this study, we continue our study and investigate the molecular basis for the differential activation of murine and human platelets by plasmin. Plasmin-induced full aggregation is achieved at lower concentrations (0.1 U/mL) in murine platelets as compared to human platelets (1 U/mL). In COS7 cells expressing the murine PAR4 (mPAR4) receptor, 1 U/mL plasmin caused a higher intracellular calcium mobilization than in cells expressing the human PAR4 (hPAR4) receptor. This difference was reversed when the tethered ligand sequences of mPAR4 and hPAR4 were interchanged through site-directed mutagenesis. This difference between human and murine PAR4 is not because of the cofactor effect of PAR3 in murine platelets by…

Advisors/Committee Members: Kunapuli, Satya P., Daniel, James L., Tuma, Ronald F. (Ronald Franklin), Autieri, Michael V., Driska, Steven Paul, Woulfe, Donna.

Subjects/Keywords: Biology, Physiology; ischemic injury; PAR1 agonist; plasmin; platelet; protease-activated receptor

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Mao, Y. (2009). ROLE OF PROTEASE-ACTIVATED RECEPTORS IN PLATELET ACTIVATION. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,47279

Chicago Manual of Style (16th Edition):

Mao, Yingying. “ROLE OF PROTEASE-ACTIVATED RECEPTORS IN PLATELET ACTIVATION.” 2009. Doctoral Dissertation, Temple University. Accessed October 22, 2020. http://digital.library.temple.edu/u?/p245801coll10,47279.

MLA Handbook (7th Edition):

Mao, Yingying. “ROLE OF PROTEASE-ACTIVATED RECEPTORS IN PLATELET ACTIVATION.” 2009. Web. 22 Oct 2020.

Vancouver:

Mao Y. ROLE OF PROTEASE-ACTIVATED RECEPTORS IN PLATELET ACTIVATION. [Internet] [Doctoral dissertation]. Temple University; 2009. [cited 2020 Oct 22]. Available from: http://digital.library.temple.edu/u?/p245801coll10,47279.

Council of Science Editors:

Mao Y. ROLE OF PROTEASE-ACTIVATED RECEPTORS IN PLATELET ACTIVATION. [Doctoral Dissertation]. Temple University; 2009. Available from: http://digital.library.temple.edu/u?/p245801coll10,47279

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