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

施莱姆管细胞连接处的 VECAD 是否可以确定 IOP 和青光眼风险？

基本信息

批准号：
10096663
负责人：
SIMON W JOHN
金额：
$ 67.28万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10096663
关键词：
Address Adherens Junction Affect Antibodies Apical Aqueous Humor Biochemical Biological Models Biology Biomechanics Blood Vessels Clustered Regularly Interspaced Short Palindromic Repeats Complex Cytoplasmic Tail Data Drainage procedure Electron Microscopy Endothelial Cells Endothelium Event Exposure to Genes Genetic Glaucoma Goals Human Immunofluorescence Immunologic Individual Intercellular Junctions Knock-in Mouse Knock-out Knowledge Label Lead Lentivirus Liquid substance Lymphatic Endothelial Cells Measures Mediating Modeling Molecular Molecular Profiling Mus Mutant Strains Mice Mutate PECAM1 gene Pathology Pathway interactions Permeability Pharmaceutical Preparations Phenylalanine Phosphoproteins Phosphorylation Physiologic Intraocular Pressure Positioning Attribute Primary Open Angle Glaucoma Process Property Proteins Regulation Resistance Resolution Risk Risk Factors Role Signal Transduction Signaling Molecule Site Structure of sinus venosus of sclera Study models Testing Tracer Translating Tyrosine Tyrosine Phosphorylation aqueous humor flow base cadherin 5 confocal imaging design high intraocular pressure improved in vivo innovation knockout gene light microscopy mechanical force mechanotransduction mutant new technology novel pressure prevent protein complex response sensor shear stress tool treatment strategy

项目摘要

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.

高眼压是青光眼的主要致病危险因素，也是当前所有青光眼的目标该项目研究控制眼压异常的途径。通过使用控制 IOP 的途径来表征这些途径导致青光眼。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。模型将增进理解并最终指导新的治疗方法。青光眼需要有效的降低眼压的治疗。施莱姆管内壁房水 (AQH) 引流阻力增加 (SC) 的内壁内皮细胞 (SEC) 是 AQH 进入血管的最终屏障。眼部血管系统对控制 AQH 流出至关重要，但批准的药物则不会。直接针对内壁或增加流出阻力的基本病理为了纠正这个问题，需要更多的 SC 生物学知识，我们将评估机械转导在确定 IOP 中的作用异常的机械转导可能会导致眼压升高和青光眼是内皮机械传导的核心因素。粘附连接复合物 (AJC)，其中 VECADHERIN (VECAD) 是一种关键蛋白质。尽管 SEC 表达 VECAD 和 AJC 蛋白，但这些蛋白在决定 AQH 流出尚未得到证实，我们将测试 VECAD 是必需的假设。 SEC 中的 AJC 机械传导，控制 AQH 流出和 IOP。我们将按照以下目标检验我们的假设：目标 1) 确定是否 AJC 蛋白磷酸化/信号传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，研究具有突变版本的小鼠。 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目标 3) 确定 VECAD 中特定酪氨酸残基磷酸化的作用。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。单个酪氨酸残基已突变为苯丙氨酸。