Caveolae-based mechanosensors for conventional outflow regulation

项目摘要 青光眼是世界范围内第二大致盲性疾病，其中原发性开角型青光眼（primary open angle glaucoma，POAG）是最常见的致盲性青光眼 是最普遍的形式。在POAG中，眼内压（IOP）升高是POAG的主要危险因素， 引起视力丧失的神经退行性变化，以及常规流出途径中的病理学， 导致眼压升高而控制常规外流的分子机制尚不清楚， 已经理解，常规流出细胞对机械刺激的稳态响应已经显示 重要. CAV 1/2基因中的多态性，其编码推定的膜必需蛋白 机械传感器，小窝，可再现地与POAG和IOP升高相关。CAV 1基因缺失 在小鼠中消融小窝，导致由于常规流出道功能缺陷引起的高眼压 功能这种缺陷的机制以及疾病相关的多态性与 Caveolae功能不清楚。该项目解决了这一重要的知识差距。以来 机械刺激人类常规流出细胞诱导小窝解体， 缺陷使传统流出道对IOP诱导的损伤更敏感，我们假设 流出道小窝是抑制IOP变化的机械敏感/机械保护平台 通过协调快速和长期的适应性细胞反应来增强流出。在aim 1中，我们将测试 假设小窝是Schlemm管中的机械传感器，其急性调节IOP， 传统的外流。在目标2中，我们将检验小凹是小梁中的机械传感器的假设， 急性调节IOP和常规流出的网状物。在最后的目标，我们将测试的假设， 小窝介导流出途径细胞中的适应性机械诱导的转录应答。的 研究表明，

Project summary Glaucoma is the second leading cause of blindness worldwide with primary open angle glaucoma (POAG) being the most prevalent form. In POAG, elevated intraocular pressure (IOP) is a primary risk factor for the neurodegenerative changes causing vision loss, and pathology in the conventional outflow pathway is responsible for elevated IOP. While the molecular mechanisms that control conventional outflow are not well understood, homeostatic responses of conventional outflow cells to mechanical stimulation have been shown important. Polymorphisms in the CAV1/2 genes, which encode essential proteins for a putative membrane mechanical sensor, caveolae, reproducibly associate with POAG and elevated IOP. Genetic deletion of CAV1 in mice ablates caveolae, resulting in ocular hypertension due to functional defects in conventional outflow function. The mechanism for this defect and the connection between disease-associated polymorphisms and caveolae function are not understood. This project addresses this important gap in knowledge. Since mechanical stimulation of human conventional outflow cells induces caveolae disassembly, and caveolae deficiency renders the conventional outflow pathway more sensitive to IOP induced injury, We hypothesize that outflow pathway caveolae are mechanosensitive/mechanoprotective platforms that transduce changes in IOP to enhance outflow by orchestrating both rapid and long-term, adaptive cellular responses. In aim 1 we will test the hypothesis that caveolae are mechanosensors in the Schlemm’s canal that acutely modulate IOP and conventional outflow. In aim 2, we will test the hypothesis that caveolae are mechanosensors in the trabecular meshwork that acutely modulate IOP and conventional outflow. In the final aim, we will test the hypothesis that caveolae mediate adaptive mechanically-induced transcriptional responses in outflow pathway cells. The studies have clear