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
This project is designed to define the mechanism(s) by which the CAV1 gene product, caveolin-1 regulates eye pressure. When altered, the caveolin locus leads to elevated eye pressure and increased risk for developing glaucoma, a major blinding eye disease in human populations. The outcome of these studies will facilitate novel therapeutic strategies to lower eye pressure and thus reduce the risk of glaucoma development and progression.
