Transcriptional Profiles of Visual System Impairment

项目摘要 在理解视网膜疾病的病因学方面存在根本性的差距，例如视网膜色素变性和 老年性黄斑变性我们理解上的这一差距由于在 潜在的遗传学，个体疾病严重程度的变化以及环境的影响。继续 该间隙的存在代表了视网膜疾病中的重要问题，因为在其被填充之前， 对这些眼病的治疗仍然是支离破碎和不完整的。长期目标是 了解不同的基因及其表达的变化如何导致视觉系统受损。 该特定应用的目的是表征一组高度近交的基因组的转录谱。 果蝇基因参考组（Drosophila Genetic Reference Panel，DGRP），并研究基因表达与果蝇基因组之间的关系。 基因组多态性与视觉系统功能和年龄相关视觉功能的实质性变化 在DGRP中的损伤。核心假设是，一个由基因共同组成的复杂遗传网络， 在这些菌株中，表达模块是造成视觉损害的原因。这一假设是基于 已发表的工作和申请人实验室产生的初步数据。建议的理由 研究是观察到多种遗传多态性已被确定在全基因组协会， DGRP中视觉系统损害的研究然而，最近的研究未能确定一个跨- 这些遗传多态性与视力损害之间的关系。使用系统遗传学 我们的假设将通过追求两个具体目标进行测试：1）识别遗传共表达 调节视觉系统功能和损伤的网络，以及2）开发和测试基因网络模型 基于这些候选共表达模块和候选基因。这种方法是创新的，因为 我们将研究基因型，转录组和视觉系统功能的相互作用，使用高度统计学方法。 Powered Systems Genetics方法结合了组织聚焦的Tag-Seq转录组分析。这个ap- 方法很可能会提供一种信息，承诺从根本上改变我们的理解， 视觉系统功能和疾病的分子遗传学。这项研究意义重大，因为它将 垂直推进我们对基因组-转录组关系及其如何影响眼睛的理解。是- 因为许多正在研究的基因与人类视网膜营养不良有关， 该项目有可能促进对视觉系统疾病的理解和治疗。

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.