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University of North Carolina

1. Fricks, Ingrid P. Molecular pharmacology and function of the P2Y14 receptor.

Degree: Pharmacology, 2009, University of North Carolina

P2Y receptors are a family of seven transmembrane spanning G protein-coupled receptors that are activated by nucleotides and nucleotide-sugars. The P2Y14-R is activated by nucleotide sugars, although little is known about the physiological role(s) of this receptor. With a view toward generating pharmacological reagents for studies of P2Y14-R, one goal of this dissertation was to apply a rational structure-activity relationship approach to develop novel ligands for the P2Y14-R. Guided by molecular modeling studies of the P2Y14-R, iterative design of synthetic ligands produced a multitude of compounds which were assessed for agonist activity at the P2Y14-R. From these studies, several novel agonists were identified for the P2Y14-R, including 2-thio-UDP-Glc, which exhibited greater than six-fold higher potency than UDP-Glc. Other novel agonists identified included several UDP-sugars. Using a COS-7 cell system in which recombinant P2Y14-R were co-expressed with the chimeric G protein, G[alpha]q/i, UDP was identified as a competitive antagonist at the P2Y14-R. In contrast, in studies comparing the pharmacological selectivity of the rat P2Y14-R to that of the human P2Y14-R in the same cell system, UDP was found to be an agonist at the rat P2Y14-R. Another goal of this work was to examine the signal transduction pathways downstream of P2Y14-R activation, and for these studies, stable cell lines expressing P2Y14-R in HEK293 and in C6 glioma cells were developed. This approach allowed study of P2Y14-R coupled to native G proteins, and P2Y14-R-dependent inhibition of adenylyl cyclase was observed. P2Y14-R activation also promoted pertussis toxin-sensitive phosphorylation of ERK1/2. Moreover, native P2Y14-R were detected in differentiated HL-60 cells by RT-PCR, and in these cells, UDP-Glc promoted pertussis toxin-sensitive activation of ERK1/2. The work presented here provides a foundation for future development of pharmacological agents for the P2Y14 receptor. Furthermore, this work establishes that the P2Y14-R couples to Gi and the MAP kinase signaling pathway, and provides robust cell model systems for future studies of P2Y14-R function. Advisors/Committee Members: Fricks, Ingrid P., Harden, T. Kendall, University of North Carolina at Chapel Hill.

Subjects/Keywords: School of Medicine; Department of Pharmacology

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

APA (6th Edition):

Fricks, I. P. (2009). Molecular pharmacology and function of the P2Y14 receptor. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:1c20c43d-a279-4023-afd5-5ebf11af62e5

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Fricks, Ingrid P. “Molecular pharmacology and function of the P2Y14 receptor.” 2009. Thesis, University of North Carolina. Accessed December 05, 2020. https://cdr.lib.unc.edu/record/uuid:1c20c43d-a279-4023-afd5-5ebf11af62e5.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Fricks, Ingrid P. “Molecular pharmacology and function of the P2Y14 receptor.” 2009. Web. 05 Dec 2020.

Vancouver:

Fricks IP. Molecular pharmacology and function of the P2Y14 receptor. [Internet] [Thesis]. University of North Carolina; 2009. [cited 2020 Dec 05]. Available from: https://cdr.lib.unc.edu/record/uuid:1c20c43d-a279-4023-afd5-5ebf11af62e5.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Fricks IP. Molecular pharmacology and function of the P2Y14 receptor. [Thesis]. University of North Carolina; 2009. Available from: https://cdr.lib.unc.edu/record/uuid:1c20c43d-a279-4023-afd5-5ebf11af62e5

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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