Does VECAD at Schlemm canal cell-junctions determine IOP and glaucoma risk?

高IOP是青光眼的一个主要因果风险因素，也是当前所有青光眼的目标 治疗该项目研究控制眼内压的途径。异常 这些途径导致青光眼。通过表征控制IOP的途径， 突变小鼠，我们期望在分子水平上更好地了解青光眼风险，并将提供 研究IOP和青光眼的重要新模型。重要监管机构的特征 模型将提高理解，并最终指导新的治疗方法。新的和更 需要有效的降低IOP的治疗。在青光眼中，IOP升高是由于 施累姆氏管内壁的房水（AQH）引流阻力增加 （SC）。SC的内壁内皮细胞（SECs）是AQH进入SC的最后屏障。 眼血管系统，并在控制AQH流出的关键。批准的药物不 直接靶向内壁或增加流出阻力的基本病理， 青光眼为了纠正这一点，需要更多的SC生物学知识，我们将评估 机械传导在确定IOP中的作用。异常的机械传导可能导致 眼压升高和青光眼内皮机械转导中的中心参与者是 粘附连接复合物（AJC），其中VECADHERIN（VECAD）是一种关键蛋白。 尽管SEC表达VECAD和AJC蛋白，但这些蛋白在决定SEC的表达中的作用是不确定的。 AQH流出尚未得到证实。我们将检验以下假设： SEC中的AJC机械转导，控制AQH流出和IOP。我们的初步数据 支持这一假设。我们将在以下目标中测试我们的假设：目标1）确定是否 AJC蛋白磷酸化/信号转导适应性地响应体内IOP变化。目标2）： 确定VECAD在体内调节IOP中的作用。研究携带突变型 VECAD将提供有关其功能的关键信息，并可能提供有价值的新模型， 青光眼目的3）确定VECAD中特定酪氨酸残基的磷酸化作用 眼压调节。我们将通过使用突变小鼠来评估关键酪氨酸在体内的作用， 单个酪氨酸残基突变为苯丙氨酸。

High IOP is a major causal risk factor for glaucoma and is the target of all current glaucoma therapies. This project investigates pathways that control intraocular pressure. Abnormalities in these pathways contribute to glaucoma. By characterizing pathways that control IOP using mutant mice, we expect to better understand glaucoma risk at a molecular level and will provide important new models for studying IOP and glaucoma. Characterization of important regulatory models will improve understanding and ultimately guide new treatments. New and more effective IOP-lowering treatments are needed. In glaucoma, elevated IOP results from increased resistance to aqueous humor (AQH) drainage at the inner wall of Schlemm’s canal (SC). The inner- wall endothelial cells of SC (SECs) are the final barrier to AQH exit into the ocular vasculature and are critical in controlling AQH outflow. Approved medications do not directly target the inner wall or the fundamental pathology that increases outflow resistance in glaucoma. To correct this, greater knowledge of SC biology is required and we will assess the role of mechanotransduction in determining IOP. Abnormal mechanotransduction may result in elevated IOP and glaucoma. A central player in endothelial mechanotransduction is the adherens junction complex (AJC) of which VECADHERIN (VECAD) is a critical protein. Although SECs express VECAD and AJC proteins, the role of these proteins in determining AQH outflow is not yet demonstrated. We will test the hypothesis that the VECAD is required for AJC mechanotransduction in SECs, controlling AQH outflow and IOP. Our preliminary data support this hypothesis. We will test our hypothesis in the following aims: Aim 1) Determine if AJC protein phosphorylation/ signaling adaptively responds to IOP changes in vivo. Aim 2): Determine the role of VECAD in regulating IOP in vivo. Studying mice with mutant version of VECAD will provide key information about its functions and may provide valuable new models of glaucoma. Aim 3) Determine the role of phosphorylation of specific tyrosine residues in VECAD in IOP regulation. We will assess the roles of key tyrosines in vivo by using mutant mice where individual tyrosine residues have been mutated to phenylalanine.