The K08 candidate proposes to conduct the following research project under the guidance of outstanding mentors in the fields of genetics, proteomics, and bioinformatics. Retinal detachment (RD) is a significant cause of legal blindness in the US, with a lifetime risk of 1/300. Proliferative vitreoretinopathy (PVR) is a scarring condition that forms in 5-10% of RD. PVR results in failure of surgical RD repair and blindness. There is no effective pharmacologic therapy for PVR. It is not known why some individuals develop PVR despite good surgical intervention and why others do not. Polymorphisms in genes important to the pathogenesis of PVR may explain this difference. My long-term goal is to develop an effective treatment to inhibit or prevent PVR. To perform this research I have created two animal models of PVR. Using the mass spectrometry technique iTRAQ, my preliminary proteomic analysis of retina and vitreous in an animal model of PVR has identified up-regulation of MIF, as well as other candidates, in PVR. Disease-relevant polymorphisms of MIF have been identified which are associated with more severe fibrosis in patients with diseases such as scleroderma. Thus, I will test the hypothesis that specific genetic polymorphisms predispose certain RD patients to PVR development. My immediate primary goals are to evaluate the timecourse of MIF up- regulation in the RD-PVR animal model and to determine the qualitative and quantitative differences in proteins, with known association with MIF signaling, in human PVR. My long-term goals are to determine the impact of modulating MIF on the development of experimental animal PVR, to identify protein networks and gene polymorphisms that lead to PVR, and to identify proteins that can be targeted by therapy. The three specific aims are: (1) Test the hypothesis that MIF is up-regulated in both human and animal model PVR. (2) Test the hypothesis that disease-associated polymorphisms of MIF are more prevalent in RD patients with PVR than without PVR. (3) Test the hypothesis that other iTRAQ candidates are up- regulated in PVR. Scientific and Clinical Impact. There is no drug treatment available for PVR. By identifying key genetic components of PVR we may remove a critical barrier to therapy by identifying novel anti-proliferative treatment targets that successflly inhibit PVR fibrosis. We may also identify biomarkers to detect patients at higher risk for PVR. The knowledge gained on the genetic basis of RD-PVR may also lead to a better understanding of other blinding fibrotic retinal diseases such as macular degeneration, ROP, and proliferative diabetic retinopathy.
Project Narrative: Proliferative vitreoretinopathy (PVR) is a blinding disorder affecting 5-10% of all patients with retinal detachment. There is no effective pharmacologic treatment for this disease. This proposal will evaluate underlying genetic and related protein changes providing the basis for PVR development, with a future goal to identify proteins that can be effectively targeted by therapy.
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