Project Grant F31EY039120

THE IMPACT OF GAQ SIGNALING ON INTRAOCULAR PRESSURE - PROJECT SUMMARY PRIMARY OPEN-ANGLE GLAUCOMA (POAG) IS THE MOST COMMON FORM OF GLAUCOMA AND A LEADING CAUSE OF IRREVERSIBLE BLINDNESS WORLDWIDE. ELEVATED INTRAOCULAR PRESSURE (IOP), THE MOST SIGNIFICANT MODIFIABLE AND CLINICALLY APPROVED RISK FACTOR FOR POAG, RESULTS FROM IMPAIRED AQUEOUS HUMOR DRAINAGE THROUGH THE TRABECULAR MESHWORK (TM), A TISSUE THAT BECOMES STIFFENED DUE TO INCREASED ACTIN POLYMERIZATION AND EXTRACELLULAR MATRIX (ECM) REMODELING. WHILE CURRENT IOP-LOWERING TREATMENTS EXIST, THEY ARE OFTEN ACCOMPANIED BY ADVERSE SIDE EFFECTS AND FAIL TO ADDRESS THE UNDERLYING BIOMECHANICAL DYSFUNCTION OF THE TM, HIGHLIGHTING THE NEED FOR SAFER AND MORE TARGETED THERAPIES. THIS PROJECT INVESTIGATES THE ROLE OF GAQ SIGNALING, AND ITS UPSTREAM MEDIATOR ENDOTHELIN-1 (ET-1), IN PROMOTING ACTIN-BASED CONTRACTILITY AND ECM REMODELING IN THE TM, CONTRIBUTING TO INCREASED IOP. PRELIMINARY STUDIES SUGGEST THAT PHARMACOLOGIC INHIBITORS OF GAQ, YM-254890 AND FR900359, REDUCE ACTIN POLYMERIZATION AND LOWER IOP, IDENTIFYING GAQ AS A PROMISING THERAPEUTIC TARGET. THE CENTRAL HYPOTHESIS IS THAT THE PHARMACOLOGICAL INACTIVATION OF GAQ CAN PREVENT IOP ELEVATION BY REDUCING THE ET SIGNALING VIA ET RECEPTORS, THUS PREVENTING BLINDNESS IN GLAUCOMA. AIM 1 WILL ASSESS THE IMPACT OF GAQ INHIBITION ON TM BIOMECHANICS AND IOP IN VIVO. AIM 2 WILL INVESTIGATE THE ROLE OF GAQ-MEDIATED SIGNALING IN ET- 1-INDUCED IOP ELEVATION AND GLAUCOMA. BY ELUCIDATING THE MECHANISTIC ROLE OF GAQ AND ET-1 SIGNALING IN TM DYSFUNCTION, THIS WORK MAY LEAD TO THE DEVELOPMENT OF NOVEL, MECHANISM-BASED THERAPIES TO OPTIMIZE TREATMENT FOR POAG IN PATIENTS AND REDUCE THE GLOBAL BURDEN OF GLAUCOMA.