High IOP is a major causal risk factor for glaucoma and is the target of all current glaucoma therapies. This project investigates pathways that control intraocular pressure. Abnormalities in these pathways contribute to glaucoma. By characterizing pathways that control IOP using mutant mice, we expect to better understand glaucoma risk at a molecular level and will provide important new models for studying IOP and glaucoma. Characterization of important regulatory models will improve understanding and ultimately guide new treatments. New and more effective IOP-lowering treatments are needed. In glaucoma, elevated IOP results from increased resistance to aqueous humor (AQH) drainage at the inner wall of Schlemm?s canal (SC). The inner- wall endothelial cells of SC (SECs) are the final barrier to AQH exit into the ocular vasculature and are critical in controlling AQH outflow. Approved medications do not directly target the inner wall or the fundamental pathology that increases outflow resistance in glaucoma. To correct this, greater knowledge of SC biology is required and we will assess the role of mechanotransduction in determining IOP. Abnormal mechanotransduction may result in elevated IOP and glaucoma. A central player in endothelial mechanotransduction is the adherens junction complex (AJC) of which VECADHERIN (VECAD) is a critical protein. Although SECs express VECAD and AJC proteins, the role of these proteins in determining AQH outflow is not yet demonstrated. We will test the hypothesis that the VECAD is required for AJC mechanotransduction in SECs, controlling AQH outflow and IOP. Our preliminary data support this hypothesis. We will test our hypothesis in the following aims:
Aim 1) Determine if AJC protein phosphorylation/ signaling adaptively responds to IOP changes in vivo.
Aim 2) : Determine the role of VECAD in regulating IOP in vivo. Studying mice with mutant version of VECAD will provide key information about its functions and may provide valuable new models of glaucoma.
Aim 3) Determine the role of phosphorylation of specific tyrosine residues in VECAD in IOP regulation. We will assess the roles of key tyrosines in vivo by using mutant mice where individual tyrosine residues have been mutated to phenylalanine.
High intraocular pressure is a key risk factor for glaucoma. This application will define and critically test key molecular events that control intraocular pressure and that act to lessen its magnitude by increasing ocular fluid drainage or outflow. Understanding these molecular processes will ultimately lead to a rational design of new treatment strategies to prevent glaucoma.
