Glaucoma is an optic neuropathy that affects nearly 67 million people world-wide. It is commonly associated with elevated levels of intraocular pressure due to a reduction in aqueous humor outflow from the trabecular meshwork (TM). Recent studies indicate that the actin cytoskeleton has a profound influence on aqueous humor outflow and thus might provide a new target for the treatment for glaucoma. Integrin/syndecan mediated signaling pathways play a critical role in regulating the actin cytoskeleton. We propose that integrins and/or syndecans contribute to the regulation of the actin cytoskeleton and outflow facility and that these receptors may be responsible for changes in the cytoskeleton (i.e., CLAN formation) observed after steroid treatment. We further propose that steroid treatment activates these signaling pathways because it causes an upregulation of extracellular ligands or cytoplasmic signaling molecules associated with integrins and syndecans. The main objectives of this grant are to determine the role that integrins and syndecans play in governing the organization of the actin cytoskeleton in the TM and the extent to which they can be manipulated to regulate outflow facility.
The aims of this grant are (1) determine the specific integrins responsible for the formation of CLANs in TM by using integrin specific peptides (agonists and antagonists) and activating or inhibiting antibodies to block or trigger CLAN formation, (2) use integrin antagonists and agonists to demonstrate that specific integrin signaling pathways influence outflow facility, especially in steroid treated eyes, (3) demonstrate that syndecan-4 is a key regulator of actin networks in the TM by blocking or enhancing its normal function using syndecan-4 siRNA and overexpression of full length or truncated syndecan-4 in TM cell cultures, (4) determine if virally expressed hairpin siRNA sequences to syndecan-4 would block steroid induced clan formation and decreases in outflow facility, and (5) determine if steroid treatment affects the expression or activity of proteins (Rac1, Tiam1, Trio, PI-3 kinase, Src, PIP2) associated with these pathways. Ultimately, this knowledge can be used to develop new therapies to treat or prevent POAG or steroid-induced glaucoma. ? ? ? ?
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