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: 10058444
• 负责人: Christine A Curcio
• 金额: $ 56.35万
• 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/10058444
• 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; Diagnostic; 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; 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.

视觉需要眼睛所有部分之间协调一致。最重要的是 对于图像的正常感知来说，视网膜是最重要的部分。这是一个 眼球背部表面的精确分层结构，包括 数以百万计的细胞聚集在一起，形成一个紧密的网络。视神经 连接视网膜和大脑。视网膜不仅能接受光线，还能 对其进行处理，并将下游信号传输到中脑和丘脑。 当视网膜发生病变时，如老年性黄斑变性 (AMD)，不幸的结果可能是失明，这是最令人恐惧的残疾。 在AMD的遗传学方面取得了实质性的进展，但这些基因的翻译 结果在临床上进展缓慢。这一延误的原因包括缺乏 由于解剖学原因，适合进行功能遗传学的动物模型 与人类的不同，对特定细胞类型的了解不足 参与AMD的发生和对人类视网膜的不完全理解 生物学。评估AMD的早期病理是否影响不同的细胞是具有挑战性的 群体与高度特定的细胞类型。最近在技术上的突破 单细胞rna-seq(scRNA-seq)使基因测量成为可能 在单个细胞中表达，为探索细胞异质性铺平了道路。 与阿拉巴马州眼科银行合作，我们将深入采集人类视网膜样本 细胞和RPE/脉络膜，充分表征细胞多样性，并阐明功能 AMD全基因组关联研究结果的作用。我们建议 遵循目标。目标1将从20岁的眼睛中产生单个和批量的RNA-SEQ数据 健康成人，24名早/中期AMD和6名GA捐赠者。目标2将 研究正常人视网膜和视网膜组织细胞多样性和细胞基因表达 RPE/脉络膜，并将这些结果与AMD眼进行比较。目标3将推断细胞类型 特定的eQTL，并将这些结果与AMD Gwas整合，以确定目标 基因。这些开创性的研究利用了新的方法和跨学科 鉴定人类视网膜和视网膜细胞类型特异性基因表达的专业知识 支持组织。通过对四个单元图集的详细描述 人眼中的地理区域，我们的研究将为细胞- 类型特定的功能，可以支持AMD的精确治疗靶向。