An interdisciplinary consortium of investigators from the Departments of Pharmacology, Ophthalmology and Biomedical Engineering at Case Western Reserve University in collaboration with the University of Cincinnati Drug Discovery Center, Washington University and the University of Pennsylvania, proposes """"""""to increase the pace at which basic science discoveries on disease mechanisms can be translated into therapies for complex visual system disorders and disease"""""""", a stated goal of the R24 National Eye Institute (NEI) Translational Research Program on Therapy for Visual Disorders. This scientific partnership will employ its diverse scientific expertise to characterize and test potential therapies for retinal diseases in animal models by using a combination of cutting-edge physiological, chemical, analytical and imaging approaches. By screening Food and Drug Administration (FDA)-approved drugs for their ability to prevent retinal pathology in animal models that mimic Stargardt's disease, age-related macular degeneration (AMD), and retinitis pigmentosa (RP), 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) Test FDA-approved drugs for their ability to reduce toxic levels of all-trans-retinal in the eye and prevent its condensation to harmful conjugates;(2) Evaluate analogues of FDA-approved drugs as potential lead compounds for treating retinal diseases by using approved compounds found effective and safe in animal model studies;(3) Assess the bioavailability and distribution of these agents to determine their ability to penetrate and remain in the eyes without affecting normal phototransduction and visual cycle reactions;and (4) Explore different modes of drug delivery and develop novel biodegradable polymers that provide therapeutic drug concentrations in the eyes. Ultimately, the experimental results of these interrelated aims will guide us in developing more successful therapies for patients affected by currently incurable blinding diseases.

Public Health Relevance

The number of persons who are legally blind in the USA exceeds 1.3 million with about 8-10 million aging persons who will be affected with age-related macular degeneration (AMD). Utilizing a mechanistically relevant model of Stargardt's disease, we have demonstrated rapid screening to potentially repurpose a broad set of FDA approved molecules. This proposal offers a compelling opportunity to attack this grievous riisfiasfi and nthsr cnnditinn.c;inditriinn AMD.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Resource-Related Research Projects (R24)
Project #
1R24EY021126-01
Application #
8018234
Study Section
Special Emphasis Panel (ZEY1-VSN (10))
Program Officer
Neuhold, Lisa
Project Start
2010-09-30
Project End
2015-08-31
Budget Start
2010-09-30
Budget End
2011-08-31
Support Year
1
Fiscal Year
2010
Total Cost
$1,931,032
Indirect Cost
Name
Case Western Reserve University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Kiser, Philip D; Zhang, Jianye; Sharma, Aditya et al. (2018) Retinoid isomerase inhibitors impair but do not block mammalian cone photoreceptor function. J Gen Physiol 150:571-590
Tonade, Deoye; Liu, Haitao; Palczewski, Krzysztof et al. (2017) Photoreceptor cells produce inflammatory products that contribute to retinal vascular permeability in a mouse model of diabetes. Diabetologia 60:2111-2120
Gulati, Sahil; Jastrzebska, Beata; Banerjee, Surajit et al. (2017) Photocyclic behavior of rhodopsin induced by an atypical isomerization mechanism. Proc Natl Acad Sci U S A 114:E2608-E2615
Jastrzebska, Beata; Comar, William D; Kaliszewski, Megan J et al. (2017) A G Protein-Coupled Receptor Dimerization Interface in Human Cone Opsins. Biochemistry 56:61-72
Tonade, Deoye; Kern, Timothy S (2017) Diabetes of 5 years duration does not lead to photoreceptor degeneration in the canine non-tapetal inferior-nasal retina. Exp Eye Res 162:126-128
Chen, Yu; Perusek, Lindsay; Maeda, Akiko (2016) Autophagy in light-induced retinal damage. Exp Eye Res 144:64-72
Sears, Avery E; Palczewski, Krzysztof (2016) Lecithin:Retinol Acyltransferase: A Key Enzyme Involved in the Retinoid (visual) Cycle. Biochemistry 55:3082-91
Chen, Yu; Kern, Timothy S; Kiser, Philip D et al. (2016) Eyes on systems pharmacology. Pharmacol Res 114:39-41
Frederiksen, Rikard; Nymark, Soile; Kolesnikov, Alexander V et al. (2016) Rhodopsin kinase and arrestin binding control the decay of photoactivated rhodopsin and dark adaptation of mouse rods. J Gen Physiol 148:1-11
Razafsky, David; Ward, Candace; Potter, Chloe et al. (2016) Lamin B1 and lamin B2 are long-lived proteins with distinct functions in retinal development. Mol Biol Cell 27:1928-37

Showing the most recent 10 out of 81 publications