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You searched for subject:(ADP Receptors). 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 21, 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. 21 Oct 2020.

Vancouver:

Bhavaraju K. MOLECULAR PHYSIOLOGY OF THROMBOXANE A2 GENERATION IN PLATELETS. [Internet] [Doctoral dissertation]. Temple University; 2010. [cited 2020 Oct 21]. 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. Bynagari, Yamini Saraswathy. Molecular Physiology of Novel Class of Protein Kinase C isoforms in Platelets.

Degree: PhD, 2010, Temple University

Molecular and Cellular Physiology

Platelets are primary components of hemostasis. However, incongruous activation of platelets lead to thrombosis, which result in multiple cardio-vascular and cerebrovascular complications. Thus, platelet activation is tightly regulated. Molecular components that aid in activation of platelets have been extensively studied. However, molecular pathways that negatively regulate platelet activation and prevent accidental activation of platelets are poorly understood. In this study we investigated the molecular mechanisms that negatively regulate platelet activation. Protein Kinase C isforms (PKCs) are serine threonine kinases that regulate various platelet functional responses leading to hemostasis. Positive regulatory role of PKCs towards platelet aggregation and secretion has been extensively studied. However, we have recently demonstrated that PKCs negatively regulate ADP- induced thromboxane generation. The PKC isoforms and mechanism involved in this process have not been known. Thus, in this study we investigated the mechanism by which PKCs negatively regulate ADP-induced thromboxane generation and identified PKC isoforms that regulate thromboxane generation. Thromboxane generation in platelets is a multi-step process beginning with cPLA2 activation. cPLA2 activation is the rate limiting step in the process of thromboxane generation. Furthermore, cPLA2 activation is regulated by ERK and calcium in various cell systems including platelets. PKC inhibition potentiated both cPLA2 and ERK activation, suggesting that PKCs negatively regulate thromboxane generation by regulating ERK activation, which in turn regulates cPLA2 activation. Furthermore, we have also shown that PKCs negatively regulate ADP-induced calcium mobilization. ADP activates platelets via P2Y1 and P2Y12 receptors. P2Y12 receptor-mediated signaling is shown to positively regulate P2Y1-mediated calcium mobilization in platelets. Furthermore, PKCs are shown to negatively regulate P2Y12 receptor desensitization in platelets. Thus, we investigated if PKCs regulate calcium mobilization indirectly by regulating P2Y12 receptor function. However, PKCs regulate calcium mobilization independent of P2Y12 receptor signaling. In summary we have shown that PKC isoforms negatively regulate ADP-induced thromboxane generation by regulating calcium mobilization and ERK activation that in turn regulates cPLA2 activity. We further investigated the PKC isoforms involved in this process. Based on our results with Go-6976, a classical PKC inhibitor and GF109203X, a pan PKC inhibitor, we identified that that novel or atypical PKC isoforms are involved in negative regulation of ADP-induced thromboxane generation. Thus, we investigated the role of various novel class of PKC isoforms (nPKCs) in platelets. We first investigated the nPKCs activated by ADP. In aspirin-treated platelets, ADP failed to activate nPKC θ and δ non-stirring conditions. Thus, we conclude that these isoforms are not involved in negative regulation of thromboxane…

Advisors/Committee Members: Kunapuli, Satya P., Driska, Steven Paul, Eguchi, Satoru, Daniel, James L., Bray, Paul F..

Subjects/Keywords: Biology, Cell; Biology, Physiology; ADP receptors; Phosphatases; Platelet signaling; Protein Kinase C; thromboxane

Record DetailsSimilar RecordsGoogle PlusoneFacebookTwitterCiteULikeMendeleyreddit

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

APA (6th Edition):

Bynagari, Y. S. (2010). Molecular Physiology of Novel Class of Protein Kinase C isoforms in Platelets. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,103230

Chicago Manual of Style (16th Edition):

Bynagari, Yamini Saraswathy. “Molecular Physiology of Novel Class of Protein Kinase C isoforms in Platelets.” 2010. Doctoral Dissertation, Temple University. Accessed October 21, 2020. http://digital.library.temple.edu/u?/p245801coll10,103230.

MLA Handbook (7th Edition):

Bynagari, Yamini Saraswathy. “Molecular Physiology of Novel Class of Protein Kinase C isoforms in Platelets.” 2010. Web. 21 Oct 2020.

Vancouver:

Bynagari YS. Molecular Physiology of Novel Class of Protein Kinase C isoforms in Platelets. [Internet] [Doctoral dissertation]. Temple University; 2010. [cited 2020 Oct 21]. Available from: http://digital.library.temple.edu/u?/p245801coll10,103230.

Council of Science Editors:

Bynagari YS. Molecular Physiology of Novel Class of Protein Kinase C isoforms in Platelets. [Doctoral Dissertation]. Temple University; 2010. Available from: http://digital.library.temple.edu/u?/p245801coll10,103230

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