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

眼前段发育不全(ASD)是一种眼部发育异常，可累及多个 组织，包括角膜、虹膜、晶状体、睫状体和眼部引流结构，包括小梁 网络(TM)。因此，ASD与青光眼和角膜混浊的风险增加有关。在……里面 事实上，50%的ASD患者会由于房水体液引流中断而出现青光眼，这 导致眼压升高。颈椎前段结构畸形 眼球的发生被认为是由于眼周间充质的分化和迁移缺陷所致。 (POM)，是神经波峰的衍生品。尽管不适当的POM图案强烈地牵涉到 在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 激活转录因子β(AP-2β)在慢性前列腺癌及其衍生组织中高表达。 小老鼠的眼睛。在之前的资助期间，我们创建了两个小鼠模型，在其中Tfap2b(基因 编码AP-2β)在POM中被有条件地删除。这两款车型的特征都让人联想到 人类自闭症和青光眼。然而，一个模型表现为虹膜角膜完全粘连，另一个模型表现为完全虹膜角膜粘连。 具有部分闭合角度的表型，但在这两个模型中，TM区域受到严重影响。我们进一步 利用这些模型之一来识别可能影响AP-2β下游的重要候选基因 眼球前部结构的发育。目前的提议旨在利用这些新的模式来进一步 确定AP-2β功能丧失如何导致下游发育缺陷和改变 控制眼睛前角结构的形成的调节网络，这些结构在 管理房水流出。因此，我们的主要假设是AP-2β调节的基因在 POM对于控制眼球前段结构的发育是必不可少的。 维持眼压动态平衡的眼睛。在目前的提案中，我们将继续使用有条件的KO 在小鼠中确定AP-2β基因在前角发育中所起个体作用的方法(S) 角状组织，包括TM。我们还将使用最先进的“组学”水平分析来确定 眼前节正常基因表达的模式以及Tfap2b的丢失如何扰乱它们。 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，以进一步 了解闭角型青光眼和视神经病变的病理生理学。

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.