PDGF and PVR

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DESCRIPTION (provided by applicant): Proliferative vitreoretinopathy is a blinding condition for which available treatment options do not address the needs of all affected patients. This application's objective is to identify new therapeutic targets and thereby guide development of drugs to prevent and/or treat PVR. Activation of platelet-derived growth factor (PDGF) receptor ??? (PDGFR??) drives experimental PVR, and is associated with this disease in humans. Antioxidants protect rabbits from developing PVR and prevent vitreous-mediated activation of PDGFR??. Furthermore, the unique ability of vitreous to chronically activate PDGFR?? is intrinsic to PVR pathogenesis. Taken together, these observations are basis of our working hypothesis that vitreous persistently activates PDGFR?? by causing an enduring elevation of ROS. In the course of aim 1 we will identify those vitreous-stimulated enzymes that are required to chronically elevate ROS and activate PDGFR??, and we will assess their potential as therapeutic targets. One of the signaling events that are required for experimental PVR is activation of phosphatidylinositol 3 kinase (PI3K). While both PDGFR?? and PDGFR?? activate PI3K in response to vitreous, only PDGFR?? induces PVR. Our working hypothesis is that PDGFR?? unceasingly activates Ras, which is required for persistent and robust activation of PI3K. In aim 2 of the grant we will deploy a combination of molecular and biochemical approaches to identify those signaling events by which PDGFR?? engages PI3K. Vitreous-induced signaling events trigger cellular responses intrinsic to PVR that include proliferation, contraction, and protection from apoptosis and senescence. For instance, signaling events that constitute pathway #1 are necessary and sufficient for a subset of these cellular responses (protection from apoptosis and senescence). In contrast, while pathway #1 is necessary for proliferation and contraction, it does not suffice. In aim 3 we will use a combination of molecular and pharmacological approaches to identify the additional signaling events (pathway #2) that are required for vitreous-mediated proliferation and contraction. The aims of this proposal are: Specific Aim 1 Determine how vitreous chronically activates PDGFR??. Specific Aim 2 Investigate the mechanism by which vitreous persistently activates PI3K/Akt. Specific Aim 3 Identify members of pathway #2, which is required for vitreous-mediated proliferation and contraction. This proposal's central hypothesis is that perpetrators of vitreous-dependent activation of PDGFR?? and downstream signaling events constitute an Achilles heel of PVR. The proposed studies will test this hypothesis by molecularly resolving key signaling events in PVR pathogenesis and assessing if they are viable targets for PVR prophylaxis.