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

高眼压是青光眼的主要致病危险因素，也是目前所有青光眼的目标。 治疗。这个项目研究控制眼压的途径。中的异常现象 这些途径导致了青光眼。通过描述控制眼压的途径 突变小鼠，我们希望在分子水平上更好地了解青光眼风险，并将提供 研究眼压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。新的和更多 需要有效的降眼压治疗。在青光眼中，高眼压是由 Schlemm管内壁对房水引流的抵抗力增加 (SC)。SC的内壁内皮细胞(SECs)是AQH进入血管的最后屏障。 眼部血管系统，在控制AQH外流方面起着关键作用。经批准的药物不会 直接针对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 机械转导在眼压测定中的作用。异常的机械转导可能导致 眼压升高和青光眼。内皮细胞机械转导中的一个中心角色是 黏附连接复合体(AJC)是其中的关键蛋白VECADHERIN(VECAD)。 虽然Secs表达VECAD和AJC蛋白，但这些蛋白在决定 AQH流出尚未证实。我们将测试这一假设，即VECAD是 AJC机械转导秒，控制AQH流出和眼压。我们的初步数据 支持这一假设。我们将在以下目标中检验我们的假设：目标1)确定 AJC蛋白磷酸化/信号转导对体内眼压变化具有适应性反应。目标2)： 确定VECAD在体内调节眼压中的作用。研究突变版本的小鼠 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)确定特定酪氨酸残基的磷酸化在VECAD中的作用 在眼压调节方面。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 个别酪氨酸残基已突变为苯丙氨酸。

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.