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Caveolae-based mechanosensors for conventional outflow regulation

用于传统流出调节的基于小凹的机械传感器

基本信息

批准号：
9596193
负责人：
MICHAEL H ELLIOTT
金额：
$ 49.86万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9596193
关键词：
Actins Acute Address Biological Assay Blindness CAV1 gene Caveolae Caveolins Cell Culture Techniques Cell membrane Cells Defect Development Disease Endothelium Enterobacteria phage P1 Cre recombinase Eye Eye diseases Gene Targeting Gene Transfer Genes Genetic Genetic Polymorphism Genetic Transcription Glaucoma Human In Situ Injury Knockout Mice Knowledge Luc Gene Mechanical Stimulation Mechanics Mediating Membrane Molecular Mus Nerve Degeneration Ocular Hypertension Organelles Outcome Study Pathology Pathway interactions Pharmacology Physiologic Intraocular Pressure Population Primary Open Angle Glaucoma Proteins Proteomics Regulation Reporter Resistance Risk Risk Factors Scaffolding Protein Signal Transduction Smooth Muscle Actin Staining Method Stress Fibers Structure of sinus venosus of sclera Testing Tissues Trabecular meshwork structure Virus base caveolin 1 cell injury design experimental study gene product in vivo monolayer novel therapeutics overexpression pressure response rho sensor targeted treatment

项目摘要

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

项目概要青光眼是全球第二大失明原因，其中原发性开角型青光眼 (POAG) 是最普遍的形式。在 POAG 中，眼压 (IOP) 升高是发生 POAG 的主要危险因素神经退行性变化导致视力丧失，而常规流出途径的病理学是导致眼压升高。虽然控制常规流出的分子机制并不完善据了解，传统流出细胞对机械刺激的稳态反应已被证明重要的。 CAV1/2 基因的多态性，该基因编码假定膜的必需蛋白质机械传感器、小窝可重复地与 POAG 和升高的 IOP 相关。 CAV1基因缺失在小鼠中消除小窝，由于传统流出的功能缺陷而导致高眼压功能。这种缺陷的机制以及疾病相关多态性与疾病之间的联系凹穴功能尚不清楚。该项目解决了这一重要的知识空白。自从人类常规流出细胞的机械刺激诱导小凹解体，并且小凹缺陷使得传统的流出途径对 IOP 引起的损伤更加敏感，我们假设流出通路小凹是机械敏感/机械保护平台，可传导眼压变化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凹是施莱姆管中的机械传感器，可以敏锐地调节眼压和常规流出。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能够敏锐调节眼压和传统血流的网络。在最终目标中，我们将检验以下假设：小凹介导流出途径细胞中适应性机械诱导的转录反应。这研究已明确