Use of Small Molecules to Control Extracellular Matrix Homeostasis
A major risk factor for glaucoma is an elevation of intraocular pressure caused by the reduced movement of fluid out of the eye. In some cases, this movement is restricted because the passageways that allow fluid to exit the eye are clogged with too much protein. The goals of this research are to understand how these proteins are deposited in these passageways and to identify ways to prevent the proteins from being deposited.
My laboratory is investigating ways to prevent the abnormal buildup of proteins in the eye that can cause glaucoma. These proteins are called extracellular matrix (ECM) proteins and are found outside of cells, where they can act as filters to regulate the flow of fluid out of the eye. When too many of these proteins are produced, they block the drainage of fluid out of the eye and it is this accumulation of fluid that causes the pressure in the eye to increase. My laboratory is investigating whether small molecules which bind a protein called fibronectin, or its receptor, can prevent the accumulation of these ECM proteins. Fibronectin is one of the major proteins found in ECM and plays a key role in regulating the assembly of other proteins into the ECM. We propose that if we inhibit its expression, that may serve to block the incorporation of other proteins into the matrix and the flow of fluid out of the eye, thereby decreasing eye pressure. To test this hypothesis we have identified several small molecules that bind fibronectin. In the first aim, we plan to use cells in culture to determine which of these small molecules can prevent the accumulation of ECM proteins that block the drainage of fluid from the eye. In the second aim, we plan to test if these small molecules can be used to control the flow of fluid out of an organ-cultured eye model that shows an elevation in pressure over time due to the accumulation of these proteins. If our study is successful, we will have identified a new way to treat certain types of glaucoma. The research also will enhance our understanding of how these ECM proteins interact with each other.