Primary open-angle glaucoma (POAG) is a group of optic neuropathies characterized by slow, progressive degeneration of retinal ganglion cells (RGCs). The resulting optic nerve damage can result in vision loss and blindness. Increased intraocular pressure (IOP) and age are the leading risk factors for both POAG development and progression. The molecular mechanism of RGC death in glaucoma is still not well understood.

Extensive collaborative efforts have described the genetic association between the glaucoma risk and specific genomic loci, including SIX1-SIX6 and 9p21, the locus most strongly associated with POAG. Recently, we used a mouse model system to study the effects of Six6 in glaucoma pathogenesis. We observed that upon increased IOP, expression of Six6 increases and directly regulates the expression of p16Ink4a, leading to enhanced RGC senescence and most likely directly causing RGC death. Our results indicate p16INK4a as a downstream integrator of diverse signals, such as inherited genetic risk, age and intraocular pressure, in the pathogenesis of glaucoma (see Molecular Cell, 2015 for details).

To decipher molecular mechanisms underlying retina biology using molecular and cellular approaches and to understand the molecular pathways involved in the disease development, we study genome-wide roles of key transcriptional regulators and changes in chromatin organization in healthy and glaucomatous retinas. Our current efforts are focused on understanding the transcriptomic and epigenetic changes associated with neurodegeneration and aging to describe molecular pathways underlying pathological processes age related eye diseases. Finally, using mouse models of glaucoma, we try to develop various therapeutic approaches that could help attenuate or stop disease progression in glaucoma patients.