Vision requires an orchestrated coordination between all parts of the eye. Of all the parts, the retina is the most vital for normal perception of an image. It is a precisely layered structure lining the surface of the back of the eye, comprising many millions of cells packed together in a tightly knit network. The optic nerve connects the retina with the brain. The retina not only receives light, but also processes it, and transmits downstream signals to the midbrain and the thalamus. When the retina becomes diseased as in age-related macular degeneration (AMD), the unfortunate result can be blindness which is the most feared disability. Progress in the genetics of AMD has been substantial, yet the translation of these results has been slow to reach the clinic. Reasons for this delay include lack of suitable animal models to perform functional genetics because of anatomical differences with humans, insufficient understanding about the specific cell types involved in the initiation of AMD and an incomplete understanding of human retinal biology. It is challenging to assess if the early pathology in AMD affects diverse cell populations versus highly specific cell types. Recent technologic breakthroughs in single-cell RNA-seq (scRNA-seq) have made it possible to measure gene expression in single cells, paving the way for exploring cellular heterogeneity. Collaborating with the Alabama Eye Bank, we will deeply sample human retinal cells and RPE/choroid, fully characterize cell diversity, and elucidate the functional roles of findings from genome- wide association studies for AMD. We propose the following aims.
Aim 1 will generate single and bulk RNA-seq data from eyes of 20 healthy adults, 24 early/intermediate AMD and 6 GA donors.
Aim 2 will characterize cell diversity and cell gene expression in normal human retina and RPE/choroid, and compare these results to AMD eyes.
Aim 3 will infer cell-type specific eQTLs and integrate these results with AMD GWAS to identify target genes. These pioneering studies leverage novel methods and interdisciplinary expertise to characterize cell type-specific gene expression in human retina and supporting tissues. By detailed characterization of the cell atlases in four geographical areas in human eye, our study will provide novel insights into cell- type specific functions that can power precision therapeutic targeting of AMD.

Public Health Relevance

Diseases that affect the retina and supporting structures are complex and it remains challenging to assess if pathological phenotypes originate in diverse cell populations or highly specific cell types. This application will address the urgent need to collect and analyze cells from postmortem human eyes to address the question about which cell types are involved in AMD.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Shen, Grace L
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University of Pennsylvania
Schools of Medicine
United States
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