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Thesis Format

Monograph

Degree

Master of Science

Program

Medical Biophysics

Supervisor

McGuire, John

Abstract

The synthetic peptide trans-cinnamoyl-leucine-isoleucine-glycine-arginine-leucine-ornithine-amide (tcLIGRLO) causes smooth muscle contraction in mouse femoral arteries. The identity of the receptor that mediates this response is undetermined. We hypothesize that the novel mechanism for tcLIGRLO-induced contractions involves a G-protein coupled receptor (GPCR) and a Gq-Ca2+ signalling pathway. Chapter 2 describes experiments using femoral arteries isolated from male and female systemic protease-activated receptor 2 (PAR2KO) mice (n=31; 21 – 39 weeks of age) using tcLIGRLO and the Gq-inhibitor, YM-254890 (YM). Contractions produced by tcLIGRLO did not differ by sex but decreased as age increased. YM inhibited tcLIGRLO-induced contractions. Chapter 3 describes preliminary work to identify a human GPCR for tcLIGRLO, other than PAR2, using the TANGO assay to screen four candidates. We identified a potential human GPCR target that warrants additional study. In conclusion, tcLIGRLO activates a novel mechanism involving a Gq-coupled receptor. This novel mechanism may have potential significance in vascular biology.

Summary for Lay Audience

We have a test compound called tcLIGRLO that causes smooth muscle contraction in a mouse artery. We do not know how the compound works but we believe it is a novel receptor for which no drugs have yet been designed to target. We used a compound called YM to block the pathways for a common type of receptor called G-protein coupled receptors or GPCRs. We found YM blocked our test compound. We also screened some candidate human GPCRs as targets of tcLIGRLO. We found some evidence that one of these receptors was activated by tcLIGRLO. In summary, we discovered more details about a novel mechanism found in mouse blood vessels and a potential human receptor that could have relevance to human vascular pathophysiology.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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