Transcriptional Profiles of Visual System Impairment

视觉系统损伤的转录概况

• 批准号: 10407617
• 负责人: John Calvin Aldrich
• 金额: $ 19.57万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407617
• 关键词: Age; Age related macular degeneration; Aging; Back; Blindness; Candidate Disease Gene; Cell physiology; Cells; Collection; Complex; Control Locus; Data; Development; Disease; Drosophila genus; Environment; Etiology; Eye; Functional disorder; Gene Expression; Gene Expression Profile; Gene Mutation; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genetic Transcription; Genetic Variation; Genome; Genomics; Genotype; Goals; Heritability; Human; Impairment; Inbreeding; Individual; Knowledge; Laboratories; Lead; Leber' s amaurosis; Life Style; Link; Literature; Messenger RNA; Mission; Modeling; Molecular; Molecular Genetics; Mutation; Nerve Degeneration; Organism; Orthologous Gene; Outcome; Pathogenicity; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Process; Proteins; Public Health; Publishing; Quantitative Trait Loci; Research; Retina; Retinal Degeneration; Retinal Diseases; Retinal Dystrophy; Retinal Photoreceptors; Retinitis Pigmentosa; Risk Factors; Severities; Severity of illness; Smoking; Stargardt' s disease; System; Systems Biology; Technology; Testing; Tissue-Specific Gene Expression; Tissues; United States National Institutes of Health; Variant; Visual impairment; Visual system structure; Work; age related; base; cell type; compound eye; cost effective; differential expression; disability; fly; gene network; genetic analysis; genetic approach; genetic architecture; genome wide association study; genomic locus; genomic variation; innovation; network models; transcriptome; transcriptome sequencing

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.

项目摘要摘要 理解视网膜疾病的病因，例如色素性视网膜炎和 与年龄相关的黄斑变性。我们理解中的这一差距是由复杂差异的复杂差异 潜在的遗传学，个体疾病严重程度的差异以及环境的影响。继续 这种差距的存在代表了视网膜疾病中的一个重要问题，因为在填补之前， 这些眼科病理的站立和治疗将保持分散和不完整。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损害。 该特定应用的目的是表征一个高度近交面板的转录曲线 果蝇菌株（果蝇遗传参考面板，DGRP），研究基因之间的关系 压力，基因组多态性以及视觉系统功能的实质变化和与年龄有关的视觉 DGRP内的损害。中心假设是一个由基因共同组成的复杂遗传网络 表达模块负责这些菌株的视觉障碍。该假设是基于 关于申请人实验室中生产的已发表的工作和初步数据。提议的理由 研究的观察结果是，在基因组广泛的缔合中已经确定了多种遗传多态性 DGRP中视觉系统障碍的研究。但是，最近的研究未能确定 这些遗传多态性与视力障碍之间的杂志联系。使用系统遗传学 方法，我们的假设将通过追求两个具体目标来检验：我们将1）确定遗传共表达 调节视觉系统功能和障碍的网络，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 我们将使用高度统计学的基因型，转录组和视觉系统功能的相互作用 动力系统遗传学方法结合了组织聚焦的TAG-SEQ转录组分析。这个ap- PRACH可能会提供一种有望从根本上改变我们对我们的理解的信息 视觉系统功能和疾病的分子遗传学。拟议的研究很重要，因为它将 垂直提高我们对基因组转录组关系及其如何影响眼睛的理解。是- 原因许多正在研究的基因与人类视网膜营养不良有关，这是基本知识 该项目有可能提高对视觉系统疾病的理解和治疗。