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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：
10186755
负责人：
MICHAEL H ELLIOTT
金额：
$ 47.82万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10186755
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 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 therapeutic intervention 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

项目总结