Schlemm’s canal targeted-Tie2 knockdown as a mouse model of adult-onset ocular hypertension and glaucoma

施累姆氏管靶向 Tie2 敲除作为成人发病高眼压症和青光眼的小鼠模型

基本信息

批准号：
10289450
负责人：
ALEJANDRA BOSCO
金额：
$ 22.88万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10289450
关键词：
Address Adult Alleles Amacrine Cells Angiopoietins Animal Model Apoptosis Autopsy Axon Blindness CRISPR/Cas technology Cell Density Cell physiology Chronic Defect Disease Down-Regulation Drops Elderly Endothelial Cells Enterobacteria phage P1 Cre recombinase Event Eye Functional disorder Genes Genetic Glaucoma Human Hypertension In Vitro Individual Injections Interruption Investigation Knock-out Link LoxP-flanked allele Lymphatic Measures Mediating Methods Modeling Molecular Mus Mutation Nerve Nerve Degeneration Neurodegenerative Disorders Ocular Hypertension Optic Nerve Optics Pathogenesis Pathogenicity Pathway interactions Penetrance Physiologic Intraocular Pressure Preclinical Testing Primary Open Angle Glaucoma Promoter Regions Reproducibility Retina Retinal Ganglion Cells Risk Rodent Rodent Model Signal Transduction Single Nucleotide Polymorphism Staphylococcus aureus Structure Structure of sinus venosus of sclera TIE-2 Receptor Testing Time Validation Vision Visual Visual Acuity adeno-associated viral vector anterior chamber axonal degeneration base cell injury design functional decline genetic approach high intraocular pressure human disease innovation knock-down mouse model neuronal cell body nonhuman primate pre-clinical prevent primary congenital glaucoma receptor expression retinal damage retinal ganglion cell degeneration tool

Address Adult Alleles Amacrine Cells Angiopoietins Animal Model Apoptosis Autopsy Axon Blindness CRISPR/Cas technology Cell Density Cell physiology Chronic Defect Disease Down-Regulation Drops Elderly Endothelial Cells Enterobacteria phage P1 Cre recombinase Event Eye Functional disorder Genes Genetic Glaucoma Human Hypertension In Vitro Individual Injections Interruption Investigation Knock-out Link LoxP-flanked allele Lymphatic Measures Mediating Methods Modeling Molecular Mus Mutation Nerve Nerve Degeneration Neurodegenerative Disorders Ocular Hypertension Optic Nerve Optics Pathogenesis Pathogenicity Pathway interactions Penetrance Physiologic Intraocular Pressure Preclinical Testing Primary Open Angle Glaucoma Promoter Regions Reproducibility Retina Retinal Ganglion Cells Risk Rodent Rodent Model Signal Transduction Single Nucleotide Polymorphism Staphylococcus aureus Structure Structure of sinus venosus of sclera TIE-2 Receptor Testing Time Validation Vision Visual Visual Acuity adeno-associated viral vector anterior chamber axonal degeneration base cell injury design functional decline genetic approach high intraocular pressure human disease innovation knock-down mouse model neuronal cell body nonhuman primate pre-clinical prevent primary congenital glaucoma receptor expression retinal damage retinal ganglion cell degeneration tool

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项目摘要

Glaucoma causes irreversible vision loss and blindness, but we still lack understanding of the multipart mechanisms that cause and drive glaucoma progression. Animal models enable investigation of cellular and molecular players throughout disease, and are essential for testing and optimizing new treatments. There is a need for animal models that selectively model pathogenic events of human glaucoma to trigger neurodegeneration with a predictable time of onset and progression. We have developed a mouse model that selectively disrupts Schlemm’s canal (SC) expression of Tie2, which is associated with ocular hypertension and glaucoma in humans. The studies proposed here will define the timecourse, sequence and variability of functional and structural optic nerve and RGC neurodegeneration in this model. We will also develop a CRISPR/Cas9 approach to disrupt Tie2 expression in SC, which could be applied independent of genetic background. This project is expected to provide an inducible glaucoma model relevant to study the pathogenesis of ocular hypertension and neurodegeneration, and a preclinical tool to evaluate new treatments for human glaucoma.

青光眼会导致不可逆转的视力丧失和失明，但我们仍然缺乏对多部分的了解引起和驱动青光眼进展的机制。动物模型可以研究细胞和整个疾病中的分子玩家，对于测试和优化新疗法至关重要。有一个需要选择性地模拟人青光眼的致病事件以触发的动物模型神经变性，具有可预测的发作和进展时间。我们已经开发了一个鼠标模型有选择地破坏Schlemm的运河（SC）TIE2的表达，这与眼部高血压有关和人类青光眼。这里提出的研究将定义时间科学的时间，顺序和可变性该模型中的功能和结构视神经和RGC神经变性。我们还将开发一个 CRISPR/CAS9在SC中破坏TIE2表达的方法，可以独立于通用应用背景。预计该项目将提供与研究有关的诱导型青光眼模型眼高血压和神经变性的发病机理，以及评估新疗法的临床前工具对于人类青光眼。