The Role of Protease-Activated Receptor-1 and -2 Signaling in Inflammation and Vascular Injury.
Sevigny, Leila.
2010
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Abstract: Protease-activated receptors (PARs) play significant roles in various human diseases including thrombosis, sepsis, cancer, and inflammation. Attenuating the signaling of these G-protein coupled receptors holds promise for treatment of these ailments. This thesis examines the role of PAR1 and PAR2 signaling in vascular injury and inflammation. PAR1 and PAR2 are diverse receptors that play... read moreintriguing roles in vascular injury. Both receptors are upregulated in injured human vascular smooth muscle cells and atherosclerotic plaques, however little is known about the functional activity of these receptors in vascular disease and injury. Previous studies have shown that PAR1 can transactivate PAR2 and that these receptors reside in close proximity. In the present studies, in vitro co-immunoprecipitation revealed that PAR1 and PAR2 associate as a heterodimer. To dissect the functional activity of PAR1/PAR2 heterodimers in vivo, I utilized a carotid arterial ligation injury model with C57BL/6 wild-type, PAR1-/-, and PAR2-/- mice. I measured intimal and medial area 21 days after ligation injury in mice treated with vehicle or the PAR1 agonist, P1pal-13. Treatment of mice with P1pal-13 caused a massive increase in intimal hyperplasia in wild-type mice, which was significantly reduced in the PAR2 knockout strain. This suggests that both PAR1 and PAR2 mediate intimal hyperplasia in this model of carotid artery ligation. PAR2, a key factor in inflammatory response, has advanced therapeutic possibilities for treating acute and chronic inflammatory diseases of the joints, lungs, gastrointestinal tract, and vascular systems. Despite considerable effort by the pharmaceutical industry, PAR2 has proven recalcitrant to targeting by small molecule inhibitors. In this thesis, I developed a potent and specific cell-penetrating lipopeptide pepducin antagonist of PAR2, P2pal-18S, which specifically inhibits PAR2-dependent signaling in human neutrophils, colon adenocarcinoma cells, and in mouse models of inflammation. These data provide proof-of-concept that PAR2 pepducin, as exemplified by P2pal-18S, may be effective treatment for inflammation and other diseases related to PAR2 signaling. In this thesis, I employed newly developed PAR1 and PAR2 pepducins to demonstrate PAR1 and PAR2 signaling is important in inflammation and remodeling after vascular injury.
Thesis (Ph.D.)--Tufts University, 2011.
Submitted to the Dept. of Genetics.
Advisor: Athan Kuliopulos.
Committee: Philip Hinds, Gordon Huggins, Gavin Schnitzler, and Robert Flaumenhaft.
Keywords: Genetics, and Pharmacology.read less - ID:
- wp988x41h
- Component ID:
- tufts:20553
- To Cite:
- DCA Citation Guide EndNote
