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.

Public Health Relevance

PVR (proliferative vitreoretinopathy) is the primary reason for failure to correct a rhegmatogenous retinal detachment (RRD) (Han, 2008;Ryan et al., 2006). PVR is typically treated surgically, which increases the risk of re-occurrence (Campochiaro, 2006;Charteris, 1998;Glaser et al., 1987);pharmacological treatment options do not exist, despite numerous attempts to develop them (Charteris, 1995). Generating drugs that prevent RRD patients from succumbing to PVR is a major unmet challenge.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Program Officer
Neuhold, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Schepens Eye Research Institute
United States
Zip Code
Wu, Wenyi; Duan, Yajian; Ma, Gaoen et al. (2017) AAV-CRISPR/Cas9-Mediated Depletion of VEGFR2 Blocks Angiogenesis In Vitro. Invest Ophthalmol Vis Sci 58:6082-6090
Huang, Xionggao; Zhou, Guohong; Wu, Wenyi et al. (2017) Editing VEGFR2 Blocks VEGF-Induced Activation of Akt and Tube Formation. Invest Ophthalmol Vis Sci 58:1228-1236
Zhou, Guohong; Duan, Yajiang; Ma, Gaoen et al. (2017) Introduction of the MDM2 T309G Mutation in Primary Human Retinal Epithelial Cells Enhances Experimental Proliferative Vitreoretinopathy. Invest Ophthalmol Vis Sci 58:5361-5367
Wu, Wenyi; Tang, Luosheng; D'Amore, Patricia A et al. (2017) Application of CRISPR-Cas9 in eye disease. Exp Eye Res 161:116-123
Huang, Xionggao; Zhou, Guohong; Wu, Wenyi et al. (2017) Genome editing abrogates angiogenesis in vivo. Nat Commun 8:112
Duan, Yajian; Ma, Gaoen; Huang, Xionggao et al. (2016) The Clustered, Regularly Interspaced, Short Palindromic Repeats-associated Endonuclease 9 (CRISPR/Cas9)-created MDM2 T309G Mutation Enhances Vitreous-induced Expression of MDM2 and Proliferation and Survival of Cells. J Biol Chem 291:16339-47
Ma, Gaoen; Duan, Yajian; Huang, Xionggao et al. (2016) Prevention of Proliferative Vitreoretinopathy by Suppression of Phosphatidylinositol 5-Phosphate 4-Kinases. Invest Ophthalmol Vis Sci 57:3935-43
Pennock, Steven; Kim, Leo A; Kazlauskas, Andrius (2016) Vascular Endothelial Cell Growth Factor A Acts via Platelet-Derived Growth Factor Receptor ? To Promote Viability of Cells Enduring Hypoxia. Mol Cell Biol 36:2314-27
Lei, Hetian; Qian, Cynthia X; Lei, Jinghu et al. (2015) RasGAP Promotes Autophagy and Thereby Suppresses Platelet-Derived Growth Factor Receptor-Mediated Signaling Events, Cellular Responses, and Pathology. Mol Cell Biol 35:1673-85
Pennock, Steven; Haddock, Luis J; Eliott, Dean et al. (2014) Is neutralizing vitreal growth factors a viable strategy to prevent proliferative vitreoretinopathy? Prog Retin Eye Res 40:16-34

Showing the most recent 10 out of 33 publications