Glaucoma is a complex multi-factorial ocular disease characterised by damage to the lamina cribrosa (LC), a specialised region of the optic nerve head (ONH) through which retinal ganglion cell axons (RGC) exit to form the optic nerve. Structural and functional damage of the LC is primarily caused by elevated intraocular pressure (IOP >21mmHg) which triggers a process of fibrotic remodelling of the region, mediated by the resident LC cells. Our lab has recently focused on the mechanisms underlying the pro-fibrotic activation of LC fibroblasts to a myofibroblast-like phenotype within the glaucomatous LC. In response to glaucoma, LC cells exhibit a hyper-proliferative phenotype, with excessive extracellular matrix (ECM) deposition and associated ECM stiffness, pro-fibrotic marker expression, and decreased apoptosis. Such cell-associated changes are typical of fibroblast-to-myofibroblast activation and fibrotic disease progression. Our recent preliminary work has further shown altered bioenergetics or ‘metabolic reprogramming’ of LC cells in glaucoma, with utilisation of alternative energy pathways such as glycolysis and glutaminolysis. Augmented glycolysis is a key hallmark for the establishment and sustainment of an activated myofibroblastic phenotype in many forms of cancer (referred to as cancer-associated fibroblasts or CAF’s). Loss of an integral membrane protein called Caveolin-1 (Cav-1) has recently been established as a key inducer of metabolic reprogramming in CAF’s and has further become recognised for its importance in fibrosis. In the context of glaucoma, several large multi-ethnic genome wide association studies (GWAS) have identified a common sequence variant for open angle glaucoma (POAG) at 7q31, a locus which spans the CAV-1 gene. Therefore, with the importance of Cav-1 in the genetic epidemiology of POAG, trabecular meshwork physiology and IOP, and its role in fibrosis, this proposal now aims to explore the potential role of Cav-1 in metabolic reprogramming of LC fibroblasts in the context of glaucoma pathogenesis.
