Targeting ER Stress for the Treatment of Steroid and Myocilin Glaucoma
Elevation of eye pressure can lead to blindness in humans. The trabecular meshwork (TM) tissue, which drains the eye and controls eye pressure, is damaged in glaucoma, thus raising eye pressure. Our recent work identified that endoplasmic reticulum (ER) stress to the TM cells is involved in elevation of eye pressure. Specifically, we discovered that two molecules, ATF4 and CHOP, are involved in this process. In this proposal, we will test whether inhibition of these molecules via a new type of drug known as an integrated stress response inhibitor (ISRIB) that lowers eye pressure in mice and cultured TM cells.
Primary open angle glaucoma (POAG), a second leading cause of blindness in the United States, is often accompanied by elevated intraocular pressure (IOP) resulting from increased resistance to aqueous humor outflow through the trabecular meshwork (TM). It is known that chronic IOP elevation leads to loss of retinal ganglion axons and blindness. Therefore, it is important to understand the pathological mechanisms leading to IOP elevation. Although glaucomatous damage to TM is known to elevate IOP, none of the current treatments target this pathway. There is a critical need to develop novel treatments targeted at glaucomatous TM damage.
We have shown that progressive accumulation of misfolded proteins is associated with the glaucomatous TM damage and IOP elevation. Specifically, we discovered that chronic endoplasmic reticulum (ER) stress-induced ATF4/CHOP in the TM is associated with IOP elevation. Expression of ATF4 in the TM leads to significant IOP elevation and reduces outflow facility in wild type mice. In this proposal, we propose to examine whether inhibition of ATF4/CHOP pathway using an integrated stress response inhibitor (ISRIB), a selective and potent inhibitor of ATF4/CHOP pathway, reduces unfolded protein load in TM cells and prevents IOP elevation in mouse models of glaucoma.
The proposed study will directly test the therapeutic effectiveness of ISRIB on protein misfolding and reduction of elevated IOP using human TM cells and mouse models of glaucoma. This study takes advantage of recently developed mouse models of glaucoma that faithfully replicate the human disease. Tg-MYOCY437H mice developed in our laboratory provide an excellent model to discover in vivo mechanisms of protein misfolding. Using dexamethazone-induced glaucoma models (eg, steroid-induced glaucoma), we will examine whether ISRIB reduces normal (not mutant) protein accumulation in TM and prevents IOP elevation. The proposed experiments are likely to provide mechanistic insights into how inhibition of ATF4/CHOP signaling (ie, a prodeath signaling cascade) prevents unfolded protein load, which can be further explored for development of novel drug targets.
About the Researcher
My laboratory is interested in understanding the pathological mechanisms involved in glaucomatous damage to trabecular meshwork (TM), elevating IOP. Our primary focus is to understand the role of protein misfolding and its associated cellular processes including, endoplasmic reticulum (ER) stress and autophagy, in glaucomatous TM damage. We have developed two novel glaucoma mouse models, as well as established various genetic tools, to study protein misfolding and biological functions of unfolded protein response pathway and autophagy in glaucoma pathogenesis. Our lab has previously established the pathological role of ER stress in glaucomatous TM damage and IOP elevation. We are currently targeting these pathways using genetic and pharmacological manipulations for the treatment of glaucoma.
I am trained as a cell biologist and gained expertise in mouse models of glaucoma that faithfully mimic human glaucoma. Although damage to the trabecular meshwork (TM) tissue that drains the eye is known to elevate IOP, no current treatment targets the outflow pathway via TM. Ever since my graduate studies, I have been interested in understanding the glaucomatous damage to the TM and in developing disease-modifying treatments based on my understanding of these pathways. Using novel mouse models of glaucoma, we linked protein misfolding and chronic endoplasmic reticulum (ER) stress to the pathophysiology of glaucomatous damage to the TM. The current focus of my lab is to target this pathway for the development of targeted treatments.
First published on: August 24, 2017
Last modified on: June 30, 2019