New pharmacological tools to explore platelet GPR56 function

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Platelets are small cell fragments that circulate in the blood and their activation is critical for the blood clotting response. Initial platelet activation results from interactions with the collagen sub- layer that becomes exposed to the blood stream following blood vessel injury. Patients who have platelets with impaired receptiveness to collagen have severe bleeding disorders. Recently, we discovered that GPR56 (ADGRG1), a collagen-sensitive adhesion G protein-coupled receptor (AGPCR), is present on the surface of platelets and mediates their activation mechanism. AGPCRs are an understudied 33-member subfamily of GPCRs characterized in part by a bulky extracellular domain. Knowledge of how AGPCRs operate in vivo has stagnated due to a lack of available probe compounds. Consequently, I am finishing up large high throughput screens to identify novel small molecule activators and inhibitors of GPR56. Use of these compounds will expand our knowledge of both platelet biology and the AGPCR mechanism through my pharmacological investigation of GPR56 signaling in platelets. I propose two aims to advance knowledge of how GPR56 works in the platelet system: (1) Validate the new GPR56 activators and inhibitors found in my screens, and (2) utilize GPR56-specific compounds to assess how GPR56 mediates platelet signaling. Aim 1 will be accomplished using a battery of established cell-based and biochemical assays to measure GPR56 signaling. Aim 2 will examine the effects of GPR56 modulatory compounds in ex vivo human and mouse platelet assays. Blood clotting (thrombosis) is implicated in a large portion of deaths. My studies will not only provide critical insight into how blood clotting is regulated, but may also yield new classes of lead compounds that might be used to treat hematological diseases.