An interdisciplinary consortium of investigators from the Departments of Ophthalmology and Pediatrics at the University of Wisconsin in collaboration with the Northwestern University Chemistry of Life Processes Institute, Biomedical Engineering, Urology, and Pediatrics, and the University of Nebraska Center for Drug Delivery and Nanomedicine, proposes to increase the pace at which basic science discoveries on disease mechanisms can be translated into therapies for exudative age-related macular degeneration (AMD), a stated goal of the R24 National Eye Institute Translational Research Program on Therapy for Visual Disorders. This scientific partnership will employ its diverse scientific expertise to characterize and test potential therapies for exudative AMD in animal models by using a combination of cutting-edge physiological, chemical, analytical and imaging approaches. By screening novel peptides derived from endogenous inhibitors of angiogenesis for their ability to prevent neovascularization in animal models that mimic AMD, we will accelerate drug development before testing in humans. Improving drug delivery to the eye as an integral part of these experiments will also be a high priority. Specific goals of this project are to: (1) determin whether the peptide mechanisms of action in the eye are through their mimicry of these natural inhibitors;(2) Produce and identify optimal new derivatives of benchmark peptides best suited to intravitreal treatment of AMD, where these are ranked by efficacy in CNV models, individually and in combination;(3) Select and tested the most active peptide(s) and their most slowly cleared formulations for efficacy in AMD models. The best candidate(s) will undergo GLP production and then safety testing, including retinal safety to select a suitable new peptide-based entity for clinical development;and (4) Establish preclinical basis for ultimate human treatment protocol for this entity through animal models of retinal disease examined via state-of-the art in vivo retinal imaging and histopathological analysis. Ultimately, the experimental result of these interrelated aims will guide us in developing more successful therapies for those afflicted by currently incurable blinding diseases with a neovascular component.

Public Health Relevance

Identification of effective compounds that can arrest the disease state with minimal systemic side effects, and alleviate the necessity of repeated intravitreal delivery is vital for effective treatment of AMD. Utilizing a mechanistically relevant model of AMD, we have demonstrated rapid screening to test a broad set of novel peptide molecules. This proposal offers a compelling opportunity to attack exudative AMD.

National Institute of Health (NIH)
National Eye Institute (NEI)
Resource-Related Research Projects (R24)
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Special Emphasis Panel (ZEY1-VSN (05))
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Agarwal, Neeraj
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University of Wisconsin Madison
Schools of Medicine
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Dharmarajan, Subramanian; Gurel, Zafer; Wang, Shoujian et al. (2014) Bone morphogenetic protein 7 regulates reactive gliosis in retinal astrocytes and Müller glia. Mol Vis 20:1085-108
Kanavi, Mozhgan Rezaie; Darjatmoko, Soesiawati; Wang, Shoujian et al. (2014) The sustained delivery of resveratrol or a defined grape powder inhibits new blood vessel formation in a mouse model of choroidal neovascularization. Molecules 19:17578-603
Shin, Eui Seok; Huang, Qiong; Gurel, Zafer et al. (2014) High glucose alters retinal astrocytes phenotype through increased production of inflammatory cytokines and oxidative stress. PLoS One 9:e103148
Song, Wei; Wei, Qing; Liu, Wenzhong et al. (2014) A combined method to quantify the retinal metabolic rate of oxygen using photoacoustic ophthalmoscopy and optical coherence tomography. Sci Rep 4:6525
Shin, Eui Seok; Sorenson, Christine M; Sheibani, Nader (2014) PEDF expression regulates the proangiogenic and proinflammatory phenotype of the lung endothelium. Am J Physiol Lung Cell Mol Physiol 306:L620-34
Urban, Ben E; Yi, Ji; Yakovlev, Vladislav et al. (2014) Investigating femtosecond-laser-induced two-photon photoacoustic generation. J Biomed Opt 19:085001
Beasley, Selina; El-Sherbiny, Mohamed; Megyerdi, Sylvia et al. (2014) Caspase-14 expression impairs retinal pigment epithelium barrier function: potential role in diabetic macular edema. Biomed Res Int 2014:417986
Li, Hao; Dong, Biqin; Zhang, Zhen et al. (2014) A transparent broadband ultrasonic detector based on an optical micro-ring resonator for photoacoustic microscopy. Sci Rep 4:4496
Dong, Biqin; Chen, Siyu; Zhang, Zhen et al. (2014) Photoacoustic probe using a microring resonator ultrasonic sensor for endoscopic applications. Opt Lett 39:4372-5
Tripathy, Sushant; Vinokour, Elena; McMahon, Kaylin M et al. (2014) High Density Lipoprotein Nanoparticles Deliver RNAi to Endothelial Cells to Inhibit Angiogenesis. Part Part Syst Charact 31:1141-1150

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