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.

前节发育不全（ASD）是眼睛的发育异常，可能涉及多个包括角膜，虹膜，镜头，睫状体和眼引流结构在内的组织网格工作（TM）。结果，ASD与青光眼和角膜角膜细胞的风险增加有关。事实，由于幽默排水的干扰，50％的ASD患者将出现青光眼，这将出现。导致眼内压（IOP）的升高。结构的畸形人们认为眼睛是由于周期性杂物的分化和迁移的缺陷而发生的（POM），神经rest的衍生物。尽管POM的不适当图案与 ASD尚不清楚ASD的POM功能和/或破坏的机制。我们的实验室表明激活转录因子β（AP-2β）在后的POM和POM衍生组织中高度表达出生小鼠眼。在上一个资金期间，我们创建了两个鼠标模型，其中TFAP2B（基因在POM中有条件地删除了编码AP-2β）。这些模型都表现出提醒人ASD和青光眼。但是，一个模型带有完整的虹膜粘合剂，另一个模型在部分闭合角表型中，但在这两种模型中，TM区域都受到严重影响。我们进一步利用这些模型之一来识别可能影响的重要的，候选的下游基因前眼结构的发展。当前的提案旨在采用这些新型模型来进一步确定AP-2β功能的丧失如何导致发育缺陷和下游改变控制眼前角度结构形成的调节网络，这对于管理水口。这就是我们的总体假设是AP-2β调节的遗传级联 POM对于控制眼前部分的开发至关重要保持IOP稳态的眼睛。在当前的提案中，我们将继续利用有条件的KO 小鼠的方法是确定AP-2β基因在前部发展的个体作用包括TM在内的角组织。我们还将使用最先进的“ OMIC”级别分析来确定前段中正常基因表达的模式以及如何因TFAP2B的丢失而破坏它们。最后，我们将进一步评估在生成的小鼠模型中观察到的青光眼变化了解闭角青光眼和视神经病的病理生理。

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

Relationship between neural crest cell specification and rare ocular diseases.

DOI：
10.1002/jnr.24245
发表时间：
2019-01
期刊：
Journal of neuroscience research
影响因子：
4.2
作者：
Akula M;Park JW;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

Progressive Loss of Retinal Ganglion Cells in Activating Protein-2β Neural Crest Cell Knockout Mice.