This is a new application for a R01. The long-term objective of this grant is to demonstrate that regulating fibronectin fibril formation can be used o prevent the increased deposition of extracellular matrix (ECM) and ocular hypertension caused by TGFbeta2 in the trabecular meshwork. TGF-b2 has recently emerged as a risk factor for primary open angle glaucoma (POAG). It is a multi-functional protein that affects several biological activities of the trabecular meshwork (TM) including increasing the synthesis of several ECM proteins. This increase in ECM is believed to restrict the outflow of aqueous humor from the TM and alter the contractile properties of the TM. This results in elevated levels of intraocular pressure which account for least 90% of glaucomas. To date, there are very few drugs that can specifically reduce ECM deposition in the TM with the goal of increasing aqueous humor outflow. To test the hypothesis that regulating fibronectin fibrillogenesis can be used to control ECM homeostasis and increase outflow facility, TGFb2 treated TM cells and organ cultured anterior segments together with a mouse overexpressing TGFb2 will be used as a model of glaucoma.
The specific aims will be to (1) test the hypothesis that the molecular inhibitors of fibrillogenesis pUR4 and R1R2 can the deposition of ECM proteins induced by TGF-b2, (2) determine if these inhibitors will decrease the contractile properties of trabecular meshwork cells, (3) determine whether these inhibitors could reverse the effects of TGFb2 and maintain normal outflow facility in organ cultured anterior segments, and (4) show that these inhibitors will prevent the TGFb2 -induced ocular hypertension in a mouse model overexpressing TGFb2 . In support of this hypothesis, preliminary data in our laboratory show that pUR4 prevented the deposition of fibronectin and laminin into the ECM of TM cultures caused by TGF-b2. It also prevented the TGFb2-induced increase in pressure in a porcine organ anterior segment culture. If successful, these studies will enhance our understanding of how ECM remodeling is controlled in the TM and identified a novel way to control the remodeling of the ECM and possibly restore function to the TM. Finally, these studies should show whether small peptides, recently identified as effective treatments for vascular eye diseases, could also represent a new class of treatments for glaucoma.
Glaucoma is the second most common cause of blindness in the U.S. and the most common cause of blindness among African-Americans. An increase in the formation of the extracellular matrix in the trabecular meshwork is thought to be one cause for the restriction in outflow facility and an increase in intraocular pressure. The goal of this project is to identify ways to reduce the formation of the extracellular matrix in the trabecular meshwork and determine if these mechanisms can be used as potential therapies to increase outflow facility.
| Keller, Kate E; Bhattacharya, Sanjoy K; Borrás, Theresa et al. (2018) Consensus recommendations for trabecular meshwork cell isolation, characterization and culture. Exp Eye Res 171:164-173 |
| Filla, Mark S; Faralli, Jennifer A; Peotter, Jennifer L et al. (2017) The role of integrins in glaucoma. Exp Eye Res 158:124-136 |
| Filla, Mark S; Dimeo, Kaylee D; Tong, Tiegang et al. (2017) Disruption of fibronectin matrix affects type IV collagen, fibrillin and laminin deposition into extracellular matrix of human trabecular meshwork (HTM) cells. Exp Eye Res 165:7-19 |
| Peotter, Jennifer L; Phillips, Jenny; Tong, Tiegang et al. (2016) Involvement of Tiam1, RhoG and ELMO2/ILK in Rac1-mediated phagocytosis in human trabecular meshwork cells. Exp Cell Res 347:301-11 |
