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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

基本信息

批准号：
10242936
负责人：
Christine A Curcio
金额：
$ 58万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/10242936
关键词：
Address Adult Affect Age related macular degeneration Alabama Alleles Alzheimer&apos 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

项目摘要

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.

视觉需要眼睛各部分之间的协调。所有的