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Title page for ETD etd-11152013-134828

Type of Document Dissertation
Author Young, Summer Elizabeth
URN etd-11152013-134828
Title Modulation of thrombin receptor signaling
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Richard M. Breyer Committee Chair
Craig W. Lindsley Committee Member
H. Alex Brown Committee Member
Heidi E. Hamm Committee Member
John A. Oates Committee Member
Kathleen L. Gould Committee Member
P. Jeffrey Conn Committee Member
  • protease-activated receptor
  • thrombosis
  • thrombin receptors
Date of Defense 2013-08-20
Availability unrestricted
The platelet thrombin receptors Protease-activated receptor 1 (PAR1) and Protease activated receptor 4 (PAR4) stand at the intersection of coagulation and platelet activation. Thrombin receptors are thus excellent pharmacological targets for the prevention of thrombosis. PAR1 antagonists show promise in clinical trials for the prevention of stroke, myocardial infarction, and death. However, like all anti-platelet therapeutics, PAR1 antagonism carries an increased risk for bleeding. PAR4, the low affinity thrombin receptor, is the next logical target. However, the field lacks a good pharmacological probe thus the role of PAR4 in thrombosis remains unknown.

Described herein is the characterization of modulators of thrombin receptor signaling by distinct entities. The modulation of PAR1 by Activated protein C, though intriguing, fails to differ from thrombin mediated PAR1 activation. Optimization of a high-throughput screen for novel PAR1 antagonists yielded novel structures for the development of future PAR1 inhibitory compounds. One inhibitory compound, o,p ddd, was found to not only inhibit PAR1 but also PAR4 and collagen mediated platelet activation through complex mechanisms. In addition, the design, synthesis, and characterization of indole based, selective PAR4 antagonists is also described.

Approved: Professor Heidi E. Hamm

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