Caveolae-Based Mechanosensors for Conventional Outflow Regulation

Project summary Glaucoma is the second leading cause of blindness worldwide with primary open angle glaucoma (POAG) being the most prevalent form. The primary risk factor for POAG, elevated intraocular pressure (IOP), results from pathology in the conventional outflow pathway. The IOP-dependent mechanical responsiveness of the conventional outflow tissue is critical to the homeostatic maintenance of IOP in the normal range, however, the mechanosensors and their transduction pathways, are not well-understood. In this project, we will examine one mechanical sensor, caveolae, which we have found to play important roles in outflow cell contractile processes. Gene variants at the CAV1/2 genes, which encode the essential proteins for caveolae formation, reproducibly associate with POAG and, importantly, with IOP elevation. Ablation of CAV1 both globally and in outflow cell-specific contexts results in ocular hypertension and defects in aqueous humor drainage from the conventional outflow pathway. The cell-intrinsic mechanisms by which caveolae transduce responses to IOP fluctuations and the connection between CAV1/2 gene variants not understood and this project expands on our prior work to address these gaps in our understanding. We hypothesize that outflow pathway caveolae are mechanosensitive/mechanoprotective platforms that transduce changes in IOP in the trabecular meshwork, the Schlemm’s canal, and in the distal outlow pathway vasculature to dynamically regulate aqueous humor drainage and thereby modulate IOP. We also predict that POAG-associated CAV1/2 risk variants impact the mechanically-induced transcriptional program to build caveolae. The successful completion of these studies has clear