Primary open angle glaucoma (POAG), a major cause of irreversible blindness, is often associated with elevated intraocular pressure (IOP) due to increased aqueous humor outflow resistance at the trabecular meshwork (TM). The pathological mechanisms leading to glaucomatous TM damage and IOP elevation are poorly understood. We have previously linked protein misfolding and endoplasmic reticulum (ER) stress to development of glaucomatous TM damage and IOP elevation. Importantly, we demonstrated that targeting abnormal myocilin accumulation and ER stress via small chemical chaperone, sodium 4-phenylbutyrate (PBA) rescues mouse model of myocilin glaucoma, which accounts for ~4% of general POAG. Our long-term goal is to determine whether PBA can be used for the treatment of the general POAG cases. Increased accumulation of extracellular matrix (ECM) due to reduced activity of matrix metalloproteinases (MMPs) that degrade extracellular ECM is implicated in the pathophysiology of general POAG. We have recently demonstrated that increased ECM accumulation induces chronic ER stress in the TM of POAG. Moreover, our preliminary studies suggest that PBA reduces ECM accumulation via induction and activation of MMPs. It is our central premise that increased ECM accumulation induces chronic ER stress, leading to TM dysfunction and IOP elevation in POAG and PBA reduces ECM accumulation and ER stress via induction and activation of MMPs. To test this hypothesis, we will utilize primary human TM cells and mouse models of glucocorticoid (GC) or TGF?2-induced ocular hypertension and human perfusion cultured POAG eyes. Both GC or TGF?2 are known to be involved in the pathophysiology of glaucomatous TM damage via increased outflow resistance and increased ECM accumulation in the TM. Based on our preliminary data that GCs activate TGF?2 signaling, we will examine whether TGF?2 signaling regulates GC-induced glaucoma (Aim1). Considering the major role of TGF?2 in the pathogenesis of POAG, we will next determine whether TGF?2 induces chronic ER stress, leading to TM dysfunction and IOP elevation via genetic knockdown of key mediators of chronic ER stress (Aim 2).
In Aim 3, we will determine whether PBA improves outflow facility and prevents TGF?2-induced ocular hypertension in mice and ex-vivo human perfusion cultured eyes. We will also determine whether PBA reduces elevated IOP via its non-chaperonin activity on induction and activation of MMPs. The proposed studies will provide pathological mechanisms of TM dysfunction and target these pathologies via PBA for the treatment of general POAG. Importantly, these studies will provide an important foundation for planned clinical trials for PBA at the University of Iowa.
The successful completion of this project will lead to insight into elevated intraocular pressure, a major risk factor of the human blinding disorder, primary open angle glaucoma. The results will provide pathological mechanisms involved in glaucoma and develop sodium 4-phenybutyrate as a novel treatment for glaucoma by targeting these pathologies.!
| Kasetti, Ramesh B; Maddineni, Prabhavathi; Patel, Pinkal D et al. (2018) Transforming growth factor ?2 (TGF?2) signaling plays a key role in glucocorticoid-induced ocular hypertension. J Biol Chem 293:9854-9868 |
