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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Resource-Related Research Projects (R24)
Project #
4R24EY022883-04
Application #
9018033
Study Section
Special Emphasis Panel (ZEY1-VSN (05))
Program Officer
Agarwal, Neeraj
Project Start
2013-03-01
Project End
2018-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
4
Fiscal Year
2016
Total Cost
$1,320,393
Indirect Cost
$146,758
Name
University of Wisconsin Madison
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Li, Hao; Liu, Wenzhong; Sorenson, Christine M et al. (2017) Sustaining Intravitreal Residence With L-Arginine Peptide-Conjugated Nanocarriers. Invest Ophthalmol Vis Sci 58:5142-5150
Saghiri, Mohammad Ali; Orangi, Jafar; Asatourian, Armen et al. (2017) Calcium silicate-based cements and functional impacts of various constituents. Dent Mater J 36:8-18
Nguyen, Eric H; Daly, William T; Le, Ngoc Nhi T et al. (2017) Versatile synthetic alternatives to Matrigel for vascular toxicity screening and stem cell expansion. Nat Biomed Eng 1:
Kaluzny, Joel; Li, Hao; Liu, Wenzhong et al. (2017) Bayer Filter Snapshot Hyperspectral Fundus Camera for Human Retinal Imaging. Curr Eye Res 42:629-635
Shu, Xiao; Liu, Wenzhong; Duan, Lian et al. (2017) Spectroscopic Doppler analysis for visible-light optical coherence tomography. J Biomed Opt 22:1-8
Jamali, Nasim; Wang, Shoujian; Darjatmoko, Soesiawati R et al. (2017) Vitamin D receptor expression is essential during retinal vascular development and attenuation of neovascularization by 1, 25(OH)2D3. PLoS One 12:e0190131
Mofidi Najjar, Fayezeh; Ghadari, Rahim; Yousefi, Reza et al. (2017) Studies to reveal the nature of interactions between catalase and curcumin using computational methods and optical techniques. Int J Biol Macromol 95:550-556
Price, Tulin O; Sheibani, Nader; Shah, Gul N (2017) Regulation of high glucose-induced apoptosis of brain pericytes by mitochondrial CA VA: A specific target for prevention of diabetic cerebrovascular pathology. Biochim Biophys Acta 1863:929-935
Linsenmeier, Robert A; Zhang, Hao F (2017) Retinal oxygen: from animals to humans. Prog Retin Eye Res 58:115-151
Ibrahim, Ahmed S; Saleh, Heba; El-Shafey, Mohamed et al. (2017) Targeting of 12/15-Lipoxygenase in retinal endothelial cells, but not in monocytes/macrophages, attenuates high glucose-induced retinal leukostasis. Biochim Biophys Acta 1862:636-645

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