Deconstructing and Modeling the Single Cell Architecture of the Age-Related Macular Degeneration Retina and RPE/Choroid

年龄相关性黄斑变性视网膜和 RPE/脉络膜的单细胞结构的解构和建模

• 批准号: 10450171
• 负责人: MARGARET M DEANGELIS
• 金额: $ 57.42万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450171
• 关键词: Address; Adult; Affect; Age related macular degeneration; Alabama; Alleles; Alzheimer' s Disease; American; Anatomy; Animal Model; Animals; Architecture; Area; Atlases; Automobile Driving; Autopsy; Back; Biology; Blindness; Brain; Cancer Patient; Cell model; Cell physiology; Cells; Choroid; Clinic; Complex; Computer software; Data; Defect; Development; Diabetic Retinopathy; Disease; Disease Pathway; Eye; Eye Banks; Fright; Functional disorder; Future; Gene Expression; Genes; Genetic; Genomics; Geographic Locations; Health; Heterogeneity; Hour; Human; Image; In Vitro; Individual; Industry; Light; Location; Measurable; Measures; Metabolic; Methods; Microglia; Midbrain structure; Modeling; Molecular; Optic Nerve; Outcome; Pathologic; Pathology; Perception; Peripheral; Pharmaceutical Preparations; Phenotype; Population; Precision therapeutics; Process; Quantitative Trait Loci; Recovery; Retina; Retinal Diseases; Retinal Pigments; Role; Sampling; Signal Transduction; Structure; Structure of retinal pigment epithelium; Surface; Testing; Thalamic structure; Tissues; Translations; Vision; Visualization; cell type; computerized tools; design; differential expression; disability; disease diagnostic; genome wide association study; improved; insight; macula; novel; open source; single-cell RNA sequencing; therapeutic target; transcriptome sequencing; user-friendly; web site

Vision requires an orchestrated coordination between all parts of the eye. Of all the parts, the retina is the most vital for normal perception of an image. It is a precisely layered structure lining the surface of the back of the eye, comprising many millions of cells packed together in a tightly knit network. The optic nerve connects the retina with the brain. The retina not only receives light, but also processes it, and transmits downstream signals to the midbrain and the thalamus. When the retina becomes diseased as in age-related macular degeneration (AMD), the unfortunate result can be blindness which is the most feared disability. Progress in the genetics of AMD has been substantial, yet the translation of these results has been slow to reach the clinic. Reasons for this delay include lack of suitable animal models to perform functional genetics because of anatomical differences with humans, insufficient understanding about the specific cell types involved in the initiation of AMD and an incomplete understanding of human retinal biology. It is challenging to assess if the early pathology in AMD affects diverse cell populations versus highly specific cell types. Recent technologic breakthroughs in single-cell RNA-seq (scRNA-seq) have made it possible to measure gene expression in single cells, paving the way for exploring cellular heterogeneity. Collaborating with the Alabama Eye Bank, we will deeply sample human retinal cells and RPE/choroid, fully characterize cell diversity, and elucidate the functional roles of findings from genome- wide association studies for AMD. We propose the following aims. Aim 1 will generate single and bulk RNA-seq data from eyes of 20 healthy adults, 24 early/intermediate AMD and 6 GA donors. Aim 2 will characterize cell diversity and cell gene expression in normal human retina and RPE/choroid, and compare these results to AMD eyes. Aim 3 will infer cell-type specific eQTLs and integrate these results with AMD GWAS to identify target genes. These pioneering studies leverage novel methods and interdisciplinary expertise to characterize cell type-specific gene expression in human retina and supporting tissues. By detailed characterization of the cell atlases in four geographical areas in human eye, our study will provide novel insights into cell- type specific functions that can power precision therapeutic targeting of AMD.

视觉需要眼睛各部位之间的协调协调。所有 零件，视网膜对于对图像的正常感知最重要。是一个 精确的分层结构，衬有眼睛背面的表面，包括 数百万个单元在紧密编织的网络中包装在一起。视神经 将视网膜与大脑联系起来。视网膜不仅接收光，还可以 处理它，并将下游信号传输到中脑和丘脑。 当视网膜与年龄相关的黄斑变性中患病时 （AMD），不幸的结果可能是失明，这是最恐惧的残疾。 AMD遗传学的进展是很大的，但是这些翻译的翻译 结果一直很慢，无法到达诊所。此延迟的原因包括缺乏 合适的动物模型以执行功能遗传学，因为解剖学 与人类的差异，对特定细胞类型的理解不足 参与AMD的启动以及对人类视网膜的不完全理解 生物学。评估AMD中的早期病理是否影响各种细胞是一项挑战 种群与高度特定的细胞类型。最近的技术突破 单细胞RNA-seq（SCRNA-Seq）已使测量基因成为可能 在单个细胞中的表达，为探索细胞异质性铺平了道路。 与阿拉巴马州眼库合作，我们将深入品尝人类视网膜 细胞和RPE/脉络膜，完全表征细胞多样性，并阐明功能 基因组广泛关联研究的发现的作用。我们建议 以下目标。 AIM 1将从20眼中生成单个和散装的RNA-seq数据 健康的成年人，24个早期/中级AMD和6个GA供体。 AIM 2意志 表征正常人视网膜中细胞多样性和细胞基因表达， RPE/脉络膜，并将这些结果与AMD眼睛进行比较。 AIM 3将推断细胞类型 特定的eqtls并将这些结果与AMD GWA集成以识别目标 基因。这些开创性的研究利用新方法和跨学科的研究 表征人类视网膜中细胞类型特异性基因表达的专业知识和 支撑组织。通过详细的四个细胞图谱的表征 人眼中的地理区域，我们的研究将为细胞提供新的见解。 类型的特定功能，可以为AMD的精确治疗靶向提供动力。