Control of Trabecular Meshwork Cytoskeleton

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DESCRIPTION (provided by applicant): This is a competitive renewal for EY017006. The long-term objective of this grant is to identify cell-matrix signaling mechanisms that can be used as therapeutic targets to control steroid induced 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). Although a number of physiological factors are known to regulate outflow facility, one of the key factors that have emerged as an important regulatory mechanism for outflow facility is the contractile properties of the TM. At the present, it is unclear what molecular events regulate contractility in the TM. It is well established that the signaling properties of extracellular matrix (ECM) proteins and their receptors (integrins) play a critical role in regulating cell contractility and we proposed that activation of one or more of the components in these signaling pathways may be responsible for the formation of cross-linked actin networks (CLANs) observed in steroid induced glaucoma. Our studies have shown that dexamethasone activates this pathway during the formation of CLANs. In this competitive renewal we plan to determine if changes in outflow facility correlate with the levels of ?v?3 integrin signaling in cultured anterior segments in the presence and absence of steroids. We also plan to identify the signaling pathways utilized by dexamethasone to activate ?v?3 integrins. To aid in the identification of components that may be upregulated by steroids we plan to use quantitative phosphoproteomics to identify components of the integrin signaling pathways that are unregulated by steroid treatment and activated by both integrin and CD47 in TM cells in culture. These studies should show whether integrin signaling pathway(s) could be involved in steroid induced glaucoma. PUBLIC HEALTH RELEVANCE: Glaucoma is the second most common cause of blindness in the U.S. and the most common cause of blindness among African-Americans. Attempts to understand the cause(s) of this disease have been hampered by the lack of well defined cell culture systems. The goal of this project is to identify the signaling pathway(s) activated during steroid induced glaucoma (SIG) so we identify potential therapeutic targets to reduce SIG.