Control of Trabecular Meshwork Cytoskeleton

University Of Wisconsin-Madison, Madison WI

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Abstract

DESCRIPTION (provided by applicant): The long-term objective of this grant is to identify how to control avb3 integrin signaling mechanisms in order to develop therapeutic targets to control phagocytosis and outflow facility in glaucoma. The glaucomas, which lead to irreversible loss of retinal ganglion cells, affect approximately 67 million people worldwide. They are commonly associated with elevated levels of intraocular pressure (IOP) due to a reduction in aqueous humor outflow from the trabecular meshwork (TM). One of the major factors that have emerged as an important regulatory mechanism for outflow facility is the actin cytoskeleton. It controls a number of key biological processes involved in maintaining normal outflow facility including contractility, phagocytosis, and matrix deposition. Integrins play a central role in regulating the activity of actin cytoskeleton and our studies suggest that dysregulation of the avb3 integrin may be responsible for some of changes observed during glaucoma including decreased phagocytosis and outflow facility. We propose that this integrin may be chronically activated in glaucoma, especially steroid induced glaucoma during a process called inside-out signaling. Inside-out signaling occurs when a secondary stimulus such as dexamethasone induces the expression, or binding, of intracellular proteins to the cytoplasmic tails of the integrin subunits This binding triggers the active conformation of the integrin. Once this integrin is activated, it would cause a decrease in phagocytosis and outflow facility by triggering a Rac1/Trio pathway that prevents phagocytosis. We plan to test this hypothesis by using an activating antibody to induce the active conformation of avb3 integrin or viral vectors to overexpress an activated avb3 integrin in porcine organ cultured anterior segments. We then plan to determine if expression of this activated avb3 integrin causes a decrease in phagocytosis and outflow facility. We also plan to determine if the Rac1/Trio pathway utilized by avb3 integrin to decrease phagocytosis is involved in the decrease in outflow facility and how dexamethasone treatment causes the activation of the avb3 integrin. Finally, we plan to determine if increases in outflow facility following steroid treatment correlate with the levels of avb3 integrin expression in the TM. These studies should show whether b3 integrin signaling pathway(s) could be involved in steroid induced glaucoma and identify sites along the pathway that we can target to increase outflow facility in the diseased eye.