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Genetic Modifiers of Enhanced S-cone Syndrome –Role of the External Limiting Membrane

增强型 S 锥综合征的遗传修饰 — 外部限制膜的作用

基本信息

批准号：
10091445
负责人：
JUERGEN K. NAGGERT
金额：
$ 42.44万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10091445
关键词：
Address Adherens Junction Adult Affect Age related macular degeneration Alleles Apical Back Binding Blindness Cell membrane Cell physiology Cells Chemicals Cluster Analysis Cone Data Defect Development Diabetic Retinopathy Diffusion Disease Disease Pathway Disease Progression Disease model Dysplasia Ethylnitrosourea Event Eye Eye diseases Failure Fundus Gene Mutation Gene Proteins Genes Genetic Genetic Screening Goals High-Throughput Nucleotide Sequencing Human Image Immunofluorescence Immunologic Immunoprecipitation Inherited Intercellular Junctions Knockout Mice Knowledge Lead Leber&apos s amaurosis Location Maintenance Membrane Modeling Molecular Muller&apos s cell Mus Mutagenesis Mutate Mutation Natural History Nature Night Blindness Optical Coherence Tomography Pathologic Pathology Pathway interactions Patients Phenotype Photoreceptors Population Process Proteins Public Health Research Retina Retinal Cone Retinal Degeneration Retinal Diseases Retinal Dysplasia Retinitis Pigmentosa Rod Role Stains Structure Syndrome Testing Tight Junctions Variant Visual Acuity Visual impairment Yeasts bioinformatics tool cell type inherited retinal degeneration insight mouse model mutant novel photoreceptor degeneration precursor cell prevent recruit retinal progenitor cell single cell analysis single-cell RNA sequencing tool transcription factor transcriptome yeast two hybrid system

项目摘要

PROJECT SUMMARY/ABSTRACT Enhanced S-cone syndrome (ESCS) is an inherited retinal degeneration characterized by an increased number of S-cones, retinal dysplasia, and progressive photoreceptor degeneration leading to early night blindness and loss of visual acuity. The disease is caused by mutations in the rod-fate determining transcription factor NR2E3 in humans and the rd7 mouse model. The disease presentation is highly variable in human and dependent on genetic background in the mouse, demonstrating the existence of genetic modifiers. The mouse model demonstrates that the retinal dysplasia is intimately associated with the occurrence of breaks in the external limiting membrane (ELM), a network of adherens/tight junctions between Müller cell apical processes and photoreceptor inner segments. Fragmentation of the ELM is also observed in other retinal diseases associated with dysplasia, such as Leber's Congenital Amaurosis (LCA) due to mutations in crumbs1 (CRB1) and RP27, and in diabetic retinopathy. We have identified a genetic modifier that prevents the fragmentation of the ELM in both the rd7 mouse and the Nrl ko mouse (RP27) models. This discovery strongly suggests a causative role for the ELM fragmentation in the development of photoreceptor dysplasia and provides a tool with which to establish the mechanisms by which ELM breaks occur, how they lead to retinal dysplasia, and how this affects disease progression. In order to identify these mechanisms we will: 1) Determine the natural history of ELM junction formation and photoreceptor differentiation in wt and the rd7 model using marker analysis of cell junction proteins. 2) Identify the cell types involved in the ELM fragmentation by single cell RNAseq analysis. 3) Determine how the modifier protein alters recruitment of junctional proteins to the cell membrane. 4) Identify the molecular basis of additional genetic modifier strains that we have generated to gain further insight into the NR2E3 disease pathways.

项目总结/文摘