Retinal development, function, and disease are, to a significant degree, controlled by the pattern of genes expressed by the cells of the retina. In an effort to better understand the mechanisms regulating photoreceptor gene expression, we have been studying rhodospin and cone opsin gene regulation as model systems. Using a variety of approaches, we, and others, have defined some of the DNA elements important for rod- and cone-specific expression, have identified and cloned some of the transcription factors that bind to these DNA elements, and have shown that mutations in some of these factors can both interfere with normal photoreceptor development in the mouse and can cause retinal degeneration in man. This application for continued funding of these studies proposes to broaden the work by taking a more systems-oriented approach. The proposed work includes three aims.
In Aim 1 we propose to analyze rod gene expression networks at the single-cell level during development and degeneration. This will aid in characterizing rod photoreceptor heterogeneity and in defining the regulatory gene expression networks within rods.
In Aim 2 we will analyze alternative RNA splicing networks during development and degeneration. Combined informatics and experimental approaches will be utilized to define the cis-elements and trans-factors that regulate retinal alternative splicing.
In Aim 3 we will analyze the activity of enhancr networks during development and degeneration. As part of this aim we will also strive to define the specific regulatory elements that constitute rod-enriched enhancers. We hope that these complementary aims will together deepen our understanding of the gene expression mechanisms underlying rod photoreceptor development, and provide insight into how alterations in gene expression and RNA splicing contribute to the cause and course of retinal degeneration.
The goal of this project is to understand how photoreceptor gene expression is regulated, and how abnormalities of gene expression are associated with retinal disease. Compared to our prior studies which focused on rhodopsin expression as a model system, the studies proposed in this renewal application are more broadly oriented, focusing on patterns of photoreceptor gene expression at the single cell level, alternative splicing, and chromatin-based enhancer elements. Information gained from these studies will hopefully provide new insights into the mechanisms of retinal disease, and may help to develop new treatment approaches for the retinal degenerative diseases.
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