The long-term goal of the proposed project is to enable development of improved treatments for retinal pigment epithelium (RPE) diseases. The RPE plays a critical role in function and maintenance of the posterior eye, and RPE disruption can lead to severe vision impairment and loss. Many heritable retinal diseases have origins or contributions from the RPE, including monogenic diseases and age-related macular degeneration, a complex disease that is a leading cause of blindness in the western aging population. While gene augmentation therapy has previously been used to successfully treat a small number of affected individuals with RPE-associated diseases, currently there are no effective cures for the vast majority of these diseases. Hence, there is a significant need to develop generalized therapeutic approaches that would be effective in treating multiple RPE-related diseases. We have observed that numerous RPE disease phenotypes are shared among mouse models bearing mutations in cell-adhesion and extracellular matrix (ECM) molecules, suggesting that the underlying pathways/networks that are disrupted and lead to the observed pathologies might also be shared. The goal of this project is to identify the common RPE pathogenic pathways/networks that may serve as druggable targets. Identifying druggable targets that participate during the pre-symptomatic stage of the disease is particularly important, to enable development of therapies that can prevent, delay onset, or decrease the severity of RPE-associated diseases irrespective of the initial cause of the disease. Our approach is to use four mouse models with RPE-driven disease to generate comprehensive quantitative phenotypic data and global and single-cell gene-expression data, and to integrate and analyze these data using sophisticated computational methods to reveal the shared molecular and biological mechanisms associated with pre-clinical RPE pathology. This will be accomplished in three aims: 1) Assess pre-clinical and end-stage RPE-related phenotypes in the four models. 2) Identify the shared molecular and biological pathways underlying the RPE-related phenotypes in the four models. Global and single-cell gene expression analysis will be performed, and these data and the phenotype data from Aim 1 will be analyzed using computational methods to identify the shared pathways perturbed in the four models. The computational results will be verified in vivo via generation and analysis of mouse models of key shared misregulated molecules. These well-characterized models will be made available to the research community. 3) Further validate in vivo that the phenotypes and key molecules and pathways identified in Aims 1 and 2 are similarly perturbed in additional models bearing mutations in cell-adhesion and ECM molecules generated by the KOMP2 program sited at The Jackson Laboratory (JAX). Successful completion of these aims will identify common molecular and biological pathways underlying RPE-related disorders, revealing potential therapeutic targets that could be effective in a broad range of these diseases, regardless of the cause of the disease.

Public Health Relevance

Disruptions of the retinal pigment epithelium (RPE), a cell layer essential for retinal function and normal vision, underlie many heritable retinal diseases and age-related macular degeneration (AMD), the leading cause of blindness in the western aging population. However, currently there are no effective cures for most RPE- related diseases. The proposed project will identify therapeutic targets potentially effective in a broad range of RPE-associated diseases by identifying the common molecular and biological pathways disrupted in four mouse models that share phenotypic characteristics of human RPE-related disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Neuhold, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Jackson Laboratory
Bar Harbor
United States
Zip Code