Crosstalk of TGF-Beta and Wnt Pathways in the Trabecular Meshwork

TGF-beta and Wnt signaling pathways are involved in intraocular pressure regulation and glaucoma pathogenesis. We are trying to identify the genes that mediate the crosstalk between the two pathways. By using these genes as therapeutic targets, we will be able manipulate both pathways at the same time and find a more effective way of restoring aqueous outflow in the TM, thereby lowering IOP and treating glaucoma.

Grantee institution at the time of this grant: University of North Texas Health Science Center

Changes in two networks of proteins—named the TGF‐beta and Wnt pathways—can promote “clogs” in the drainage system of the eye—the trabecular meshwork (TM). These clogs cause an increase in eye pressure and may lead to glaucoma. Dr. Weiming Mao and colleagues will first screen the TGF‐beta and Wnt pathways to identify the specific proteins that are involved in cross‐talk between these two networks. Then, they will test whether the TM drain structure and eye pressure can be brought back to normal after genetically increasing or decreasing the levels of these cross‐talk proteins in cultured cells and animal models of glaucoma. If one of the proteins ends up influencing eye pressure through the TGF‐beta and Wnt pathways, then a drug could be designed to better control eye pressure in glaucoma.

Progress Updates

Dr. Mao’s team has discovered that there are components that mediate the cross-talk between the TGF-Beta and Wnt protein signaling pathways in human and cow trabecular meshwork (TM) cells. They found four genes in primary human TM cells that are significantly affected by this process. In the future, the team will overexpress, knock down, or use small molecule inhibitors to investigate whether manipulation of these four genes is able to “cut-off” the cross-talk. In addition, they will test whether two other “hypothesis-driven” target genes are involved in this process.