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Development of a Murine Model to Study Inhibitors of CXCR3-Ligand Interactions

Tjoeng, Charis Geraldine (2010) Development of a Murine Model to Study Inhibitors of CXCR3-Ligand Interactions. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

CXCR3 is involved in numerous inflammatory disorders such as rheumatoid arthritis, multiple sclerosis, allograft rejection and inflammatory bowel disease. There is a strong and growing demand for novel and effective therapeutics that can mediate CXCR3 activity. In this study, a set of botanical compounds and a peptide mimetic of the second extracellular loop (ECL-2) of CXCR3 were examined for the ability to inhibit interactions between CXCR3 and its ligands in a murine model. EGCG, a green tea polyphenol, and gallotannin, derived from many plant sources, strongly inhibited the chemotaxis of stably transfected murine CXCR3-expressing L1.2 cells in response to murine CXCL9, CXCL10, and CXCL11. EGCG was also shown to bind directly to murine CXCR3 ligands with high affinities. Baicalin, a flavonoid found in the medicinal plant Scutellaria baicalensis, and ginkgolide A, from the Ginkgo biloba tree, did not significantly reduce cell migration towards murine CXCR3 ligands, nor did the peptide mimetic of the ECL-2 of murine CXCR3. Other green tea polyphenols similar in structure to EGCG were also analyzed and were less able to inhibit murine CXCR3 ligand-mediated chemotaxis than EGCG, with the following efficacies: ECG > EGC > EC. It was observed that the most effective test compounds contained more hydroxyl groups and hence were more negatively charged, similar to glycosaminoglycans, which are extracellular matrix components that bind many chemokines. It is possible that EGCG and gallotannin are able to bind the GAG-binding domains of murine CXCR3 ligands, which allows them to prevent receptor binding and inhibit their function. This possibility represents the public health relevance of this research, as EGCG and gallotannin may be attractive candidates as lead compounds for new therapeutics for CXCR3-mediated and other inflammatory diseases.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Tjoeng, Charis Geraldinectjoeng@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairReinhart, Toddreinhar@pitt.eduREINHAR
Committee MemberKalinski, Pawelkalinskip@msx.upmc.edu
Committee MemberWang, Tianyitywang@pitt.eduTYWANG
Date: 28 January 2010
Date Type: Completion
Defense Date: 25 August 2009
Approval Date: 28 January 2010
Submission Date: 31 August 2009
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Chemokines; CXCL10; CXCL11; CXCL9; inflammatory disorders
Other ID: http://etd.library.pitt.edu/ETD/available/etd-08312009-200542/, etd-08312009-200542
Date Deposited: 10 Nov 2011 20:01
Last Modified: 15 Nov 2016 13:50
URI: http://d-scholarship.pitt.edu/id/eprint/9308

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