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.

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Research Project (R01)
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Neuhold, Lisa
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Schepens Eye Research Institute
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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
Lei, Hetian; Kazlauskas, Andrius (2014) A reactive oxygen species-mediated, self-perpetuating loop persistently activates platelet-derived growth factor receptor *. Mol Cell Biol 34:110-22
Pennock, Steven; Kim, David; Mukai, Shizuo et al. (2013) Ranibizumab is a potential prophylaxis for proliferative vitreoretinopathy, a nonangiogenic blinding disease. Am J Pathol 182:1659-70
Lei, Hetian; Kazlauskas, Andrius (2013) Detection of H2O2-mediated phosphorylation of kinase-inactive PDGFR*. Methods Enzymol 528:189-94
Pennock, Steven; Kazlauskas, Andrius (2012) Vascular endothelial growth factor A competitively inhibits platelet-derived growth factor (PDGF)-dependent activation of PDGF receptor and subsequent signaling events and cellular responses. Mol Cell Biol 32:1955-66
Lei, Hetian; Velez, Gisela; Kazlauskas, Andrius (2011) Pathological signaling via platelet-derived growth factor receptor {alpha} involves chronic activation of Akt and suppression of p53. Mol Cell Biol 31:1788-99
Liu, Kun-Wei; Feng, Haizhong; Bachoo, Robert et al. (2011) SHP-2/PTPN11 mediates gliomagenesis driven by PDGFRA and INK4A/ARF aberrations in mice and humans. J Clin Invest 121:905-17
Lei, Hetian; Rheaume, Marc-Andre; Velez, Gisela et al. (2011) Expression of PDGFR* is a determinant of the PVR potential of ARPE19 cells. Invest Ophthalmol Vis Sci 52:5016-21
Pennock, Steven; Rheaume, Marc-Andre; Mukai, Shizuo et al. (2011) A novel strategy to develop therapeutic approaches to prevent proliferative vitreoretinopathy. Am J Pathol 179:2931-40
Lei, Hetian; Velez, Gisela; Cui, Jing et al. (2010) N-acetylcysteine suppresses retinal detachment in an experimental model of proliferative vitreoretinopathy. Am J Pathol 177:132-40

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