Proliferative vitreoretinopathy (PVR) occurs after retinal detachment and severe ocular trauma and leads to both pre-retinal and subretinal scar formation, one of the major determinants of poor outcomes for these patients. Importantly, PVR may be found in greater than 50% of patients with perforating injuries and in up to 10% of retinal detachment patients. Although the pathophysiology of PVR is not completely understood, current evidence implicates various cell types including the retinal pigment epithelium (RPE) in an aberrant wound healing response. The long term objectives of this work is to develop a new strategy to effectively prevent or treat this response in order to decrease the risk of blindness or permanent loss of vision from PVR. The health relatedness of this proposal is that successful completion of this work could lead to preservation of vision in affected individuals. Recent studies support the hypothesis that control EMP2 (epithelial membrane protein 2), or its downstream signaling pathway, may change the biologic response of RPE cells and prevent or treat PVR.
The specific aims proposed in this grant submission will test the hypothesis that downregulation of EMP2 or its signal transduction pathway could be effective in prevention or therapy of PVR both in vitro and in an in vivo animal model of disease. Three different approaches will be used in the animal models including an inhibitor that is used currently in cancer therapy, a designer antibody developed in our laboratory, and a small molecule inhibitor of a biochemical pathway. Successful completion of the work proposed in this grant submission will identify the optimum strategy for prevention or early therapy for PVR. Importantly this work will also define the ocular safety profile in an animal model in order to perform the preclinical studies necessary to contemplate future clinical trials in human disease. The significant impact of this work will be to identify potential therapeutic strategies for prevention of PVR through treatment at the time of initial repair of retinal detachment or perforating ocular injury or as an adjunctive agent in treatment of established PVR. It is anticipated that successful completion of the studies proposed in this grant application would form the basis of the scientific evidence that could quickly lead to clinical trials in human disease. The clinical trials, beyond the scope of the present submission, could potentially lead to new therapies and result in restoration of sight or prevention of blindness following penetrating ocular trauma or retinal detachment. This work has potential to both advance the field of research and to ultimately change the standard of care for affected individuals and is aligned with the strategic goals of improving healthcare through interdisciplinary research.
The purpose of this study is to test whether new observations made in our laboratories could be used in order to design a novel therapeutic approach for proliferative virteoretinopathy (PVR), a potentially blinding disease that is associated with severe eye trauma or retinal detachments. Epithelial membrane protein 2 (EMP2), a protein that is normally found in the eye and may be linked to development of PVR, will be targeted for decreased function using a designer antibody fragment or a small molecule inhibitor. The relevance to public health would be to use the observations that result from this study and develop a new therapy that will either prevent or effectively treat PVR.
|Telander, David G; Yu, Alfred K; Forward, Krisztina I et al. (2016) Epithelial Membrane Protein-2 in Human Proliferative Vitreoretinopathy and Epiretinal Membranes. Invest Ophthalmol Vis Sci 57:3112-7|
|Morales, Shawn A; Telander, David G; Leon, Deanna et al. (2013) Epithelial membrane protein 2 controls VEGF expression in ARPE-19 cells. Invest Ophthalmol Vis Sci 54:2367-72|
|Morales, Shawn A; Telander, David G; Mareninov, Sergey et al. (2012) Anti-EMP2 diabody blocks epithelial membrane protein 2 (EMP2) and FAK mediated collagen gel contraction in ARPE-19 cells. Exp Eye Res 102:10-6|
|Telander, David G; Morales, Shawn A; Mareninov, Sergey et al. (2011) Epithelial membrane protein-2 (EMP2) and experimental proliferative vitreoretinopathy (PVR). Curr Eye Res 36:546-52|
|Morales, Shawn A; Telander, David; Notterpek, Lucia et al. (2011) Rewiring integrin-mediated signaling and cellular response with the peripheral myelin protein 22 and epithelial membrane protein 2 components of the tetraspan web. Invest Ophthalmol Vis Sci 52:5465-72|
|Morales, Shawn A; Mareninov, Sergey; Wadehra, Madhuri et al. (2009) FAK activation and the role of epithelial membrane protein 2 (EMP2) in collagen gel contraction. Invest Ophthalmol Vis Sci 50:462-9|