Role of AP-2beta in Anterior Segment Development

AP-2beta 在眼前节发育中的作用

基本信息

批准号：
9334570
负责人：
TREVOR J WILLIAMS
金额：
$ 31.88万
依托单位：
MCMASTER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9334570
关键词：
Address African American Age Alleles Angle-Closure Glaucoma Anterior Anterior eyeball segment structure Aqueous Humor Axon Birth Blindness Cells ChIP-seq Ciliary Body Complement Factor B Cornea Corneal Opacity Corneal Stroma Data Defect Development Drainage procedure Embryo Enterobacteria phage P1 Cre recombinase Exhibits Eye Eye Development FOXC1 gene Functional disorder Gene Expression Genes Genetic Glaucoma Hispanics Individual Iris Knockout Mice Laboratories Lead Life Expectancy Measurement Mesenchyme Mus Mutant Strains Mice Neural Crest Ophthalmology Optic Nerve Patients Pattern Phenotype Physiologic Intraocular Pressure Play Population Research Retinal Risk Role Structure Structure of sinus venosus of sclera TFAP2B gene Tissues Trabecular meshwork structure Transgenes United States Visual activating transcription factor differential expression disability lens malformation migration mouse model mutant novel optic nerve disorder postnatal public health relevance transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Anterior segment dysgenesis (ASD) is a developmental anomaly of the eye that can involve multiple tissues including the cornea, iris, lens, ciliary body and ocular drainage structures including the trabecular meshwork (TM) and Schlemm's canal. As a result, ASD is associated with an increased risk of glaucoma and corneal opacities. In fact, glaucoma will arise in 50% of patients with ASD due to disruption in aqueous humour drainage, which leads to an elevation in intraocular pressure (IOP). Malformation of structures in the anterior segment of the eye is thought to occur due to a defect in the differentiation and migration of the periocular mesenchyme (POM), a derivative of neural crest. Although inappropriate patterning of the POM is strongly implicated in ASD, the mechanisms of POM function and/or disruption in ASD are unclear. Our laboratories have shown that activating transcription factor ß (AP-2ß) is highly expressed in the POM and POM-derived tissues of the post-natal mouse eye. Furthermore, we have found that conditional deletion of Tfap2b (the gene encoding AP-2ß) in the POM (using a Wnt-1 Cre driver that targets the POM of the eye) leads to a fully penetrant, angle closure glaucoma phenotype with the iris adhering to the cornea. Interestingly, our preliminary findings also show that the Wnt-1Cre/AP-2ß mutant's exhibit features of glaucoma including RGC loss and increased retinal glial reactivity. In the current proposal we will continue to utilize conditional KO approaches in mice to identify the individual role(s) that the AP-2ß gene plays in development of the anterior angle tissues including the TM and cornea. We will also use state-of-the-art "omics" level analyses to determine the patterns of normal gene expression in the anterior segment and how they are disrupted by loss of Tfap2b. Finally, we will further assess the glaucomatous changes observed in the mouse models generated to further understand the pathophysiology of closed angle glaucoma and optic neuropathy.

描述：前段失调（ASD）是眼睛的发育异常，涉及多种含量。 ASD面临着令人不安的青光眼和角膜不透明的风险。 NCHYME（POM）的元素，尽管POM的不适当形式在ASD中含义很大，但POM功能的机制和/或ASD中的纪律尚不清楚。 - 纳塔尔小鼠的眼睛。包括RGC损失的青光眼的特征在当前的提案中提高了胶质反应。和角膜分析，以确定前段中正常基因表达的模式，以及TFAP2B的损失。