The retinal degenerative (RD) diseases are a heterogeneous group of conditions that range from the Mendellian inherited orphan diseases such as retinitis pigmentosa (RP) to the genetically complex disease age-related macular degeneration (AMD). With the exception of the neovascular (wet) form of AMD, these diseases remain essentially untreatable. As one approach to both increase our understanding of these diseases and develop novel treatment strategies, we propose to perform phenotypic screens for small molecules that could serve as molecular probes and/or lead molecules for drug development. In our first aim we propose to conduct high content screens (HCS) for photoreceptor (PR) differentiation-promoting and PR neuroprotective compounds using mouse primary retinal cultures, which have significant advantages over the use of established cell lines. As proof of principle for this approach, we have successfully used this strategy in the past to identify compounds that are neuroprotective for retinal ganglion cells both in vitro and in vivo.
I aim 2, we propose a variety of secondary assays to characterize, classify and prioritize the active molecules identified in our primary screens. Another PR biological pathway that is sensitive to perturbation is the clearance of PR outer segments (OS). More than a dozen different mutations in the gene for MER tyrosine kinase (MERTK), which encodes the retinal pigment epithelial (RPE) cell receptor necessary for PR OS phagocytosis, have been shown to cause RP.
In aim 3, using an assay based upon human stem cell derived MERTK -mutant RPE cells, we will screen for compounds that can increase MERTK-independent RPE phagocytosis.

Public Health Relevance

The retinal degenerative (RD) diseases are a heterogeneous group of conditions that range from the Mendellian inherited orphan diseases such as retinitis pigmentosa (RP) to the genetically complex disease age-related macular degeneration (AMD). With the exception of the neovascular ('wet') form of AMD, these diseases remain essentially untreatable. As one approach to both increase our understanding of these diseases and develop novel treatment strategies, we propose to perform phenotypic screens for small molecules that could serve as molecular probes and/or lead molecules for drug development.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY024249-05
Application #
9609445
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Neuhold, Lisa
Project Start
2014-12-01
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
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