Caveolae-based mechanosensors for conventional outflow regulation

项目总结 青光眼是全球第二大致盲原因，伴有原发性开角型青光眼(POAG)。 是最流行的形式。在POAG中，高眼压(IOP)是主要的危险因素 神经退行性改变导致视力丧失，传统流出途径中的病理改变是 导致眼压升高。虽然控制常规外流的分子机制并不是很好 可以理解，传统的流出细胞对机械刺激的稳态反应已经显示出来。 很重要。编码膜必需蛋白的CAV1/2基因的多态性 机械感应器，小窝，可重复地与POAG和高眼压相关。冠状病毒1型的基因缺失 在小鼠中消融小窝，由于常规流出功能缺陷而导致高眼压 功能。这种缺陷的机制以及与疾病相关的基因多态和 小窝的功能还不清楚。该项目解决了这一重要的知识鸿沟。自.以来 机械刺激人常规流出细胞导致小窝解体和小窝 缺陷使传统的流出途径对眼压引起的损伤更敏感，我们假设 流出通道小窝是传递眼压变化的机械敏感/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。在目标1中，我们将测试 假设小窝是Schlemm管中的机械传感器，它尖锐地调节眼压和眼压 常规流出。在目标2中，我们将检验小凹是小梁中的机械感受器的假设 敏锐地调节眼压和常规流出的网络。在最终目标中，我们将检验假设 小凹在流出通路细胞中介导机械诱导的适应性转录反应。这个 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