The long term objectives of the proposed work is to develop new therapeutic approaches for clinical care in prevention of proliferative vitreoretinopathy following trauma or retinal detachment, both major causes for loss of vision in veterans. One cause for vision loss is ocular trauma, an unfortunately common cause of morbidity in modern warfare. Proliferative vitreoretinopathy (PVR) is found in greater than 30% of patients with perforating injuries of the eye, and is one of the major determinants of poor outcomes for these patients. Recent studies support the hypothesis that blockade of a specific protein, epithelial membrane protein 2 (EMP2), or its downstream signaling pathway, may control the biologic response of RPE cells and decrease the potential for PVR. Importantly, if this hypothesis is confirmed then this work paves the way towards developing new therapies to treat or prevent these blinding diseases. In order to test the hypothesis there are three specific aims of this proposal. 1) Characterize consequences of EMP2 blockade on retinal pigment epithelial cell (RPE) functions in vitro. In this aim established RPE cell lines will be used to study the effect of EMP2 blockade on cell survival, cell signal transduction mechanisms, and ability to contract collagen gels. In addition, this aim tests the prediction that dose synergy with reduced toxicity could be achieved through combined targeting of EMP2 and the FAK/Src pathway. 2) Evaluate the association of EMP2 and its signaling pathways in human PVR and other scarring retinal diseases. The underlying and testable hypothesis of this aim is that EMP2 and its associated signaling pathways are key players in the pathophysiologic behavior of RPE in human PVR. 3) Test prevention of PVR through blockade of EMP2 or its signaling pathways in vivo. The ultimate goal of this proposal is to complete preclinical studies to define whether, in an experimental rabbit model of PVR, blockade of EMP2 using a specific engineered anti-EMP2 antibody or FAK/Src phosphorylation using a small molecule inhibitor will abrogate experimentally-induced PVR while minimizing toxicity. It is anticipated that successful completion of the studies proposed in this application could quickly lead to clinical trials in human disease. The clinical trials, which are 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 the potential to both advance the field of research and to ultimately change the standard of care for affected individuals.
Relevance of the proposed research to Veterans health and/or healthcare issues. Vision loss is a major cause of morbidity among veterans and results from chronic or degenerative diseases such as diabetes mellitus or age-related macular degeneration as well as trauma or spontaneous retinal detachments. One major cause of blindness after ocular trauma or retinal detachment is proliferative vitreoretinopathy (PVR). Development of a specific therapy to either prevent or treat PVR, the goal of this proposal, is directly relevant to the health relatedness of the VA mission. It is anticipated that successful completion of the studies proposed in this grant application could quickly lead to clinical trials in human disease. The clinical trials, which are 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.
| Morales, Shawn A; Mareninov, Sergey; Coulam, Paige et al. (2009) Functional consequences of interactions between FAK and epithelial membrane protein 2 (EMP2). Invest Ophthalmol Vis Sci 50:4949-56 |
