权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Investigation of regulatory cascades governing development of the outflow structures of the eye

控制眼睛流出结构发育的调控级联的研究

基本信息

批准号：
10610930
负责人：
TREVOR J WILLIAMS
金额：
$ 36.41万
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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610930
关键词：
Adhesions Adult Affect Angle-Closure Glaucoma Anterior Anterior eyeball segment structure Anterior segment dysgenesis Aqueous Humor Axon Birth Blindness Candidate Disease Gene Cells Chromatin Ciliary Body Cornea Corneal Endothelium Corneal Opacity Defect Development Drainage procedure Enterobacteria phage P1 Cre recombinase Exhibits Eye Eye Development Eye diseases Functional disorder Funding Gene Expression Gene Expression Profile Genes Genetic Genetic Diseases Glaucoma Homeostasis Human Human Genetics Individual Investigation Iris Laboratories Link Liquid substance LoxP-flanked allele Maintenance Measurement Mesenchyme Modeling Morphology Mus Nature Neural Crest Optic Nerve Pathology Pathway interactions Patients Pattern Phenotype Physiologic Intraocular Pressure Play Production Regulation Retina Reverse Transcriptase Polymerase Chain Reaction Risk Role Structural defect Structure Structure of sinus venosus of sclera System TFAP2B gene Time Tissues Trabecular meshwork structure Transgenes Vision activating transcription factor aqueous aqueous humor flow cell type conditional knockout developmental disease early onset follow-up genome wide association study lens loss of function malformation migration molecular marker mouse model mutant mutant mouse model novel optic nerve disorder postnatal prevent transcription factor

项目摘要

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). 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 β (AP-2β) is highly expressed in the POM and POM-derived tissues of the post- natal mouse eye. During the previous funding period we created two mouse models in which Tfap2b (the gene encoding AP-2β) was conditionally deleted in the POM. These models both exhibit features reminiscent of human ASD and glaucoma. However, one model presents with complete iridocorneal adhesion, and the other with a partially closed angle phenotype, yet in both models the TM region is severely affected. We further utilized one of these models to identify important, candidate downstream genes of AP-2β that likely impact development of anterior eye structures. The current proposal aims to employ these novel models to further determine how loss of function of AP-2β results in developmental defects and alterations in downstream regulatory networks that control formation of the anterior angle structures of the eye, which are critical in managing aqueous outflow. Thus, our overarching hypothesis is that AP-2β-regulated genetic cascades in the POM are essential for governing development of the ocular structures in the anterior segment of the eye that maintain IOP homeostasis. In the current proposal we will continue to utilize conditional KO approaches in mice to identify the individual role(s) that the AP-2β gene plays in development of the anterior angle tissues including the TM. 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.

眼前节发育不全（ASD）是一种眼的发育异常，可涉及多个包括角膜、虹膜、透镜、睫状体的组织和包括小梁的眼引流结构网状结构（TM）。因此，ASD与青光眼和角膜混浊的风险增加有关。在事实上，由于房水引流中断，50%的ASD患者会出现青光眼，这导致眼内压（IOP）升高。前节结构畸形眼被认为是由于眼周间充质的分化和迁移缺陷而发生的 (POM)是神经嵴的衍生物。尽管POM的不适当的模式化强烈地牵涉到 ASD中POM功能和/或破坏的机制尚不清楚。我们的实验室已经证明，转录激活因子β（AP-2β）在POM和POM衍生的组织中高度表达。纳塔尔的老鼠眼。在之前的资助期间，我们创建了两个小鼠模型，其中Tfap 2b（基因编码AP-2β）在POM中条件性缺失。这些模型都展示了让人想起人类ASD和青光眼。然而，一个模型呈现完全虹膜角膜粘连，另一个模型呈现完全虹膜角膜粘连。具有部分闭角表型，但在两种模型中TM区域受到严重影响。我们进一步利用其中一个模型来鉴定AP-2β的重要候选下游基因，前眼结构的发育。目前的建议旨在利用这些新的模式，以进一步确定AP-2β功能的丧失如何导致发育缺陷和下游细胞的改变。控制眼睛前角结构形成的调节网络，这在控制房水流出。因此，我们的总体假设是，AP-2β调节的基因级联反应， POM对于控制眼前段中眼结构的发育是必不可少的，维持IOP稳态的眼睛。在当前的提案中，我们将继续使用条件KO 在小鼠中的方法，以确定AP-2β基因在前额叶发育中发挥的个体作用，角组织包括TM。我们还将使用最先进的“组学”水平分析来确定眼前节中正常基因表达的模式以及它们如何被Tfap 2b的缺失破坏。最后，我们将进一步评估在产生的小鼠模型中观察到的脑水肿变化，以进一步了解闭角型青光眼和视神经病变的病理生理。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

AP-2β is required for formation of the murine trabecular meshwork and Schlemm's canal.

DOI：
10.1016/j.exer.2020.108042
发表时间：
2020-06
期刊：
Experimental eye research
影响因子：
3.4
作者：
Akula M;Taiyab A;Deschamps P;Yee S;Ball AK;Williams T;West-Mays JA
通讯作者：
West-Mays JA

Conditional deletion of AP-2β in mouse cranial neural crest results in anterior segment dysgenesis and early-onset glaucoma.

DOI：
10.1242/dmm.025262
发表时间：
2016-08-01
期刊：
Disease models & mechanisms
影响因子：
4.3
作者：
Martino VB;Sabljic T;Deschamps P;Green RM;Akula M;Peacock E;Ball A;Williams T;West-Mays JA
通讯作者：
West-Mays JA

Deletion of transcription factor AP-2β from the developing murine trabecular meshwork region leads to progressive glaucomatous changes.

DOI：
10.1002/jnr.24982
发表时间：
2022-03
期刊：
Journal of neuroscience research
影响因子：
4.2
作者：
Taiyab A;Akula M;Dham J;Deschamps P;Sheardown H;Williams T;Borrás T;West-Mays JA
通讯作者：
West-Mays JA

Relationship between neural crest cell specification and rare ocular diseases.