The Roles of EYS in photoreceptor health

EYS 在感光器健康中的作用

基本信息

批准号：
10056405
负责人：
HUAIYU HU
金额：
$ 24.3万
依托单位：
UPSTATE MEDICAL UNIVERSITY
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 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10056405
关键词：
Animal Model Animals Applications Grants Biological Models Blindness Callithrix Callithrix jacchus jacchus Cell Therapy Cells Cilia Clinical Complex Development Disease Electroretinography Embryo Evaluation Extracellular Matrix Proteins Eye Female Future Generations Genes Genetic Diseases Genome Goals Health Homologous Gene Homologous Protein Housing Human Implant Investigational Therapies Knowledge Laboratories Litter Size Longitudinal Studies Maintenance Mammals Membrane Methods Modeling Mus Mutate Mutation Oocytes Ophthalmology Optical Coherence Tomography Photoreceptors Primates Proteins Protocols documentation Public Health Research Retina Retinal Degeneration Retinitis Pigmentosa Role Structure Study models Testing Translating Work Zebrafish assisted reproduction clinically relevant cone-rod dystrophy cost effective therapy fovea centralis genome editing knockout gene model development new therapeutic target nonhuman primate novel photoreceptor degeneration postnatal retinal imaging rodent genome therapeutic development therapeutic gene therapy development

项目摘要

Mutations in the secreted protein known as eyes shut homolog (EYS) make up a large number of autosomal recessive cases of cone-rod dystrophy and retinitis pigmentosa, retinal degeneration characterized by loss of photoreceptors. Interestingly, although present in most mammals, the rodent genome does not have a functional EYS locus. EYS protein in zebrafish is located near the connecting cilium, a structure that connects the inner and outer segment of photoreceptors and deletion of EYS causes photoreceptor degeneration in the zebrafish. Although EYS-deficient zebrafish does provide opportunities for mechanistic studies, it is a poor model for testing gene- or cell-based therapies for human retinal degeneration. This project is aimed at generating a novel EYS-deficient novel model essential for therapeutic development: Aim 1: Generation of a novel animal model bearing mutations in the EYS locus by genome editing. Aim 2: Evaluating retinal development and maturation by non-invasive assessments of structure and function: optical coherence tomography (OCT) and electroretinography (ERG). At the completion of the studies, we will have generated founder animals bearing mutations in the EYS locus. These animals will be used to generate a germline-transmitted EYS deficient retinal degeneration model in the future. They will be essential for testing gene- or cell-based therapies and for understanding how EYS deletion impacts the function and maintenance. In addition, robust protocols for non-invasive ophthalmologic and functional evaluations of the retina will be established for critical evaluation of retinal degeneration models in the future.

分泌的蛋白质中的突变被称为眼睛关闭同源物（EYS）锥体杆营养不良和视网膜炎的常染色体隐性病例，视网膜变性以失去感受器的损失为特征。有趣的是，尽管大多数哺乳动物都存在，但啮齿动物基因组没有功能性EYS基因座。斑马鱼中的Eys蛋白质位于连接纤毛，一种连接光感受器内部和外部段的结构 EYS的删除会导致斑马鱼中的感光受体变性。虽然不足斑马鱼确实为机械研究提供了机会，它是测试基因或测试基因或基于细胞的人类视网膜变性疗法。该项目旨在生成小说 Eys缺乏治疗发展至关重要的新型新型模型：目标1：通过基因组在EYS基因座中产生的新型动物模型编辑。目标2：通过非侵入性评估评估视网膜发展和成熟结构和功能：光学相干断层扫描（OCT）和电视图（ERG）。研究完成后，我们将产生带有突变的创始人动物 EYS基因座。这些动物将用于产生一种种系传输的EYS 未来的视网膜变性模型。它们对于测试基因或基于细胞的基因至关重要疗法并了解EYS删除如何影响功能和维护。在补充，可用于视网膜的非侵入性眼科和功能评估的强大方案将来将建立用于视网膜变性模型的批判性评估。