Protease Activated Receptor Type 2 Targeting for Migraine Pain

Migraine is the most common neurological disorder, the 3rd most common disease on earth, and the 8th mostdisabling. Currently available treatments fail to effectively manage migraine in most patients. Development ofnew therapeutics has been slow due in large part to a poor understanding of the underlying pathology ofmigraine. Endogenous proteases, released in the meninges by resident mast cells, have been proposed as apotential driver of migraine pain via an action on protease activated receptor type 2 (PAR2). Unfortunately theevidence for this mechanism relies on imprecise pharmacological tools and lacks genetic validation. The centralhypothesis of this multi-PI research program is that PAR2 expression in nociceptors that project to the meningesplays a key role in the pathogenesis of migraine pain by linking meningeal protease release to sensitization ofthe trigeminal nociceptive system. The primary objectives of this proposal are to develop next generation PAR2antagonists, to use these tools to validate PAR2 as a migraine pain target and to use mouse genetics to identifythe specific role of PAR2 expression in meningeal projecting nociceptors to migraine pain. Our first aim will beto use our established PAR2 development pipeline to design new PAR2 antagonists with improved drug-likeproperties to probe PAR2 function in the context of a mouse model of migraine pain. Our second aim will usepharmacological tools in a novel mouse migraine model to further understand the potential role of PAR2 inmigraine and signaling pathways engaged by PAR2 to evoke pain from the dura. Our final aim will use mousegenetics to study the cell type-specific role of PAR2 in migraine pain. Our work will result in: 1) the discovery anddevelopment of novel high potency antagonists for PAR2; 2) the development of an innovative new target formigraine pain; and 3) provide the first genetic verification of the cell type-specific action of PAR2 in the painpathway. Taken together, successful studies will provide a preclinical rationale for the further development andtesting of PAR2 ligands for the treatment of migraine and other forms of pain.