Mechanical Basis for Trabecular Meshwork Stress Response

Project Summary

The most important risk factor for developing optic nerve neuropathy in glaucoma is elevated intraocular pressure (IOP). However, it is not well understood how the cells of the trabecular meshwork (TM) recognize when the IOP is too high. The objective of this proposal is to determine how TM cells sense alterations in IOP. Dr. WuDunn's hypothesis is that the eye senses IOP through mechanical forces that act on the TM cells. When aqueous outflow channels become obstructed, fluid flow diminishes, resulting in higher IOP, which leads to increased fluid flowing through the remaining channels. The idea that shear stress may play a signaling role in IOP regulation comes from the observations that in vascular endothelium, shear stress elicits ELAM-1 expression and ELAM-1 has recently been found to be expressed in glaucomatous, but not in non-glaucomatous eyes. Dr. WuDunn suggests that shear stress might be the source of a stress response in TM cells. This hypothesis is being tested by identifying fluid flow conditions, such as oscillatory flow or cessation of flow, that elicit shear stress-mediated and cytokine-mediated stress responses in TM cells; by determining the interaction between shear stress and cytokine-mediated responses in TM cells; and by determining the role of the mobilization of intracellular calcium in fluid shear stress responses. The results from these experiments should help to better understand how TM cells detect alterations in IOP, which then allows for modification of aqueous outflow resistance. The long-term goal of this project is to understand how IOP is monitored and how it can be modulated for therapeutic purposes.