Integrative analysis of bulk and single-cell RNA-seq data from human retina for age-related macular degeneration

对来自人类视网膜的大量和单细胞 RNA-seq 数据进行综合分析，以了解与年龄相关的黄斑变性

• 批准号: 10241966
• 负责人: Mingyao Li
• 金额: $ 23.97万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241966
• 关键词: Affect; Age related macular degeneration; Alleles; Alzheimer' s Disease; American; Anatomy; Animal Model; Animals; Architecture; Autopsy; Blindness; Cancer Patient; Cell model; Cells; Code; Computer software; Data; Data Analyses; Data Set; Defect; Development; Diagnostic; Disease; Disease Pathway; Eye; Foundations; Functional disorder; Funding; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genotype; Human; In Vitro; Individual; Link; Location; Measurable; Metabolic; Methods; Molecular; National Eye Institute; Outcome; Pathology; Precision therapeutics; Proteins; Quantitative Trait Loci; Reporting; Resolution; Retina; Retinal Diseases; Role; Sampling; Single Nucleotide Polymorphism; Statistical Data Interpretation; Statistical Methods; Testing; Untranslated RNA; Variant; Vision; Visualization; cell type; computerized tools; design; drug development; genetic association; genetic variant; genome wide association study; genome-wide analysis; genomic locus; human data; novel; open source; single-cell RNA sequencing; therapeutic target; trait; transcriptome sequencing; user-friendly; web site

PROJECT SUMMARY Age-related macular degeneration (AMD) affects over 10 million Americans, twice the number affected by Alzheimer disease and equal to the total of all cancer patients combined. Worldwide, AMD is the third largest cause of vision loss. While there are short-term therapies available for one type of AMD, the underlying disease is by no means cured, and vision loss is an eventual outcome for many individuals. Although advances in retinal disease diagnostics have progressed rapidly, specific treatments for AMD directed at primary genetic or metabolic defects have progressed slowly due to a lack of understanding of the disease pathway. The slow progress is a result of multiple factors including lack of information about cell types involved in the initiation of AMD. Therefore, there is an urgent need to understand what cells are contributing to the development of AMD pathology. Identification of the cellular and gene expression changes occurring in human AMD will facilitate the design of animal and in vitro cell models incorporating the affected cell types for future drug development. While genome-wide association studies (GWAS) have identified strong and highly replicated association of genetic loci for AMD, GWAS findings can only suggest locations of associated variants and not directly link any one gene within a region to disease. Since most GWAS-identified single nucleotide polymorphisms are located in non-coding regions, their influence on disease is believed to be on modulating RNA expression by acting as expression quantitative trait loci. In this project, we propose to perform integrative secondary data analysis of publically available bulk RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) data from postmortem human retina, to test the hypothesis that measurable molecular deficits that include cell types and gene expression occur in the retina of AMD eyes. We will further integrate with publically available GWAS data on AMD to advance post-GWAS interpretation of AMD genetic results. By detailed characterization of cell type composition and cell type-specific gene expression changes in human eye, our results will elucidate the functional roles of GWAS findings that are still poorly understood and can power precision therapeutic targeting of AMD. All new computational tools will be released as user-friendly open source software. A visualization and query website will also be created to facilitate dissemination of our findings.

项目概要 年龄相关性黄斑变性 (AMD) 影响着超过 1000 万美国人，是受年龄相关性黄斑变性影响的人数的两倍 阿尔茨海默病又等于所有癌症患者的总和。 AMD 是全球第三大 视力丧失的原因。虽然有针对一种类型的 AMD 的短期疗法，但其根本原因是 疾病无法治愈，许多人的最终结果是视力丧失。虽然进步了 视网膜疾病诊断领域进展迅速，针对原发性遗传的 AMD 特异性治疗 或由于缺乏对疾病途径的了解而导致代谢缺陷进展缓慢。慢的 进展是多种因素的结果，包括缺乏有关启动细胞类型的信息 AMD。因此，迫切需要了解哪些细胞有助于AMD的发展 病理。鉴定人类 AMD 中发生的细胞和基因表达变化将有助于 设计动物和体外细胞模型，纳入受影响的细胞类型，用于未来的药物开发。 虽然全基因组关联研究（GWAS）已经确定了强且高度重复的关联 AMD 的遗传位点，GWAS 研究结果只能提示相关变异的位置，而不能直接关联任何变异 一个区域内的一个基因导致疾病。由于大多数 GWAS 鉴定的单核苷酸多态性位于 在非编码区，它们对疾病的影响被认为是通过充当 表达数量性状位点。在这个项目中，我们建议对以下内容进行综合二次数据分析： 公开的批量 RNA 测序 (RNA-seq) 和单细胞 RNA-seq (scRNA-seq) 数据来自 死后人类视网膜，以检验可测量的分子缺陷的假设，包括细胞类型和 基因表达发生在 AMD 眼睛的视网膜中。我们将进一步整合公开的GWAS数据 AMD 促进 AMD 遗传结果的 GWAS 解释。通过细胞类型的详细表征 人眼中的成分和细胞类型特异性基因表达变化，我们的结果将阐明 GWAS 研究结果的功能作用仍知之甚少，但可以为精准治疗靶向提供动力 AMD 的。所有新的计算工具都将作为用户友好的开源软件发布。可视化和 还将创建查询网站，以方便传播我们的调查结果。