PROJECT SUMMARY ABSTRACT There is a fundamental gap in understanding the etiology of retinal disorders, such as retinitis pigmentosa and age-related macular degeneration. This gap in our understanding is compounded by complex differences in the underlying genetics, variation in individual disease severity, and the effects of the environment. The continued existence of this gap represents an important problem in retinal disorders because, until it is filled, the under- standing and treatment of these eye pathologies will remain fragmented and incomplete. The long-term goal is to understand how different genes and the variation in their expression contribute to visual system impairment. The objective of this particular application is to characterize the transcriptional profile of a panel of highly inbred fruit fly strains (the Drosophila Genetic Reference Panel, DGRP) and study the relationship between gene ex- pression, genomic polymorphisms and the substantial variation in visual system function and age-related visual impairment within the DGRP. The central hypothesis is that a complex genetic network composed of gene co- expression modules is responsible for visual impairment in these strains. This hypothesis has been formed based on published work and preliminary data produced in the applicant's laboratory. The rationale for the proposed research is the observation that multiple genetic polymorphisms have been identified in Genome Wide Associa- tion Studies of visual system impairment in the DGRP. However, recent studies have failed to identify a tran- scriptional link between these genetic polymorphisms and the impairment of vision. Using a Systems Genetics approach, our hypothesis will be tested by pursuing two specific aims: We will 1) Identify Genetic Co-Expression Networks that regulate visual system function and impairment, and 2) Develop and test gene network models based on these candidate co-expression modules and candidate genes. The approach is innovative because we will examine the interactions of genotype, transcriptome and visual system function using a highly statistically powered Systems Genetics approach incorporating a tissue focused Tag-Seq transcriptome analysis. This ap- proach is likely to provide a type of information that promises to fundamentally alter our understanding of the molecular genetics of visual system function and disease. The proposed research is significant because it will vertically advance our understanding of the genome-transcriptome relationship and how it impacts the eye. Be- cause many of the genes under study are associated with human retinal dystrophies, the fundamental knowledge from the project has the potential to advance the understanding and treatment of visual system disease.

The proposed research is relevant to public health because the discovery of the pathogenic mechanisms that lead to retinal degeneration and the identification of homeostatic and compensatory mechanisms that influence the disease process is ultimately expected to increase our understanding of retinitis pigmentosa and other reti- nal disease in humans. This knowledge may be used to manipulate specific cells in the eye of patients with visual system disorders. Thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help reduce the burdens of human disability.