The atrophic ("dry") form of age-related macular degeneration (AMD), which is the most common form of the disease, is largely untreatable. Accumulating evidence suggests that dysfunction and loss of retinal pigment epithelial (RPE) cells plays an important role in the pathophysiology of AMD. Efforts have therefore been made to A) develop agents that promote RPE health and survival and B) develop cell transplantation-based approaches to replace the dysfunctional and lost RPE cells. In this application we propose to take complementary High Throughput Screening (HCS) and High Content Screening (HCS) approaches to identify small molecules that promote the survival of human stem cell-derived RPE cells exposed to oxidative stress (Specific Aim 1) and molecules that promote the differentiation of stem cells towards an RPE phenotype (Specific Aim 2). Given that oxidative stress has been implicated in AMD, the molecules identified in Aim 1 will hopefully serve as lead molecules for the development of cytoprotective approaches for dry AMD therapy. And the molecules identified in Aim 2 will hopefully aid in the development of improved cell-based treatment approaches for dry AMD. In addition, the molecules from both aims will also serve as molecular probes that will be useful in study of the mechanisms that determine RPE differentiation and that modulate the RPE cell's response to oxidative stress.

Public Health Relevance

Dysfunction and loss of retinal pigment epithelial (RPE) cells plays an important role in the pathophysiology of dry AMD. Through high throughput and high content screens of chemical libraries we propose to identify small molecules that 1) promote the survival of RPE cells exposed to oxidative stress and 2) promote the differentiation of human stem cells into RPE cells. This work will hopefully both provide insights into disease mechanisms and provide lead compounds for the development of novel treatment strategies for AMD.

National Institute of Health (NIH)
Exploratory/Developmental Grants (R21)
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Shen, Grace L
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Johns Hopkins University
Schools of Medicine
United States
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Maruotti, Julien; Sripathi, Srinivas R; Bharti, Kapil et al. (2015) Small-molecule-directed, efficient generation of retinal pigment epithelium from human pluripotent stem cells. Proc Natl Acad Sci U S A 112:10950-5
Sluch, Valentin M; Zack, Donald J (2014) Stem cells, retinal ganglion cells and glaucoma. Dev Ophthalmol 53:111-21