My research focus is to understand the pathological molecular mechanisms of glaucoma, a leading cause of irreversible blindness worldwide and to develop therapeutic targets based on the understanding of these mechanisms. Primary open angle glaucoma (POAG), the most common form of glaucoma is usually accompanied by elevated intraocular pressure (IOP). Trabecular meshwork, a specialized tissue located at the iridocorneal angle of the eye, maintains normal IOP by regulating outflow resistance. Functional failure of TM tissues is known to increase outflow resistance, elevating IOP. However, current glaucoma treatments do not address the underlying pathology of glaucomatous damage to the outflow pathway. Fully understanding the mechanisms of glaucomatous damage to the TM would greatly aid the development of "disease modifying" therapies. Myocilin, the leading genetic cause of POAG is thought to play a role in glaucomatous pathology of the TM. Establishing a genetic model of myocilin-glaucoma provides an important tool not only understand the molecular mechanisms, but also allows testing strategies for therapeutic intervention of glaucoma. We have recently generated a novel transgenic mouse model (Tg-MYOCY437H) that expresses mutant myocilin in the TM and develops glaucoma phenotypes (i.e. elevated IOP, retinal ganglion cell death, and axonal degeneration) similar to human POAG. Using this model, we have demonstrated that endoplasmic reticulum (ER) stress in the TM plays an important role in elevation of IOP and that reduction of ER stress by a small chemical chaperone, sodium 4-phenylbutyrate (PBA) rescues glaucoma (Zode et al., 2011). I am interested in further understanding the role of ER stress in the pathogenesis of myocilin-associated glaucoma as well as general POAG. I am also interested in exploring whether therapeutic targeting to reduce ER stress by PBA or other chaperones will be an effective new strategy for lowering IOP in glaucoma patients as well as improve RGC survival and function over time.
No financial relationships have been disclosed.