Tuesday, June 17, 2025
6/17/2025
Investigation of regulatory cascades governing development of the outflow structures of the eye - 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.
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