This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.To determine whether compounds that generate nitric oxide (NO) can relax carbachol contracted or resting ciliary muscle (CM) in vitro. This is an indicator of whether this class of compounds may be useful in enhancing uveoscleral outflow as an approach for lowering intraocular pressure in glaucoma. To utilize the monkey anterior segment in organ culture to investigate the effects of gene therapy and other molecules on trabecular outflow which may also be important for glaucoma therapy.Signaling pathways utilized to induce the CM relaxation response to nitric oxide donors are being determined. The effects of pretreatment with ODQ, an inhibitor of the guanylate cyclase pathway, prior to administering a nitric oxide donor, is currently under investigation. NO compounds have potential value in therapeutic areas where relaxation (NO donors) or contraction (possibly NO synthase inhibitors) of the CM is desirable, such as in the treatment of glaucoma. The monkey organ-cultured anterior segment system is being utilized to determine the effects of pharmacotherapy and gene therapy on trabecular outflow which may subsequently be utilized for glaucoma therapy to decrease intraocular pressure. Peptides derived from the heparin II domain of fibronectin are being tested for their ability to block the interaction of cellular adhesions with the surrounded extracellular matrix and to enhance trabecular outflow. Viral vectors expressing genes which target various steps involved in regulating the actin cytoskeleton are being studied. These include dominant negative (DN) Rho, DNTiam-1, DNaNcatenin. Thymosin beta 4, an endogenous monomeric actin binding protein, had no effect on outflow facility. Overexpression of the protein cochlin, which is elevated only in human glaucoma, is being studied for its effects on intraocular pressure (IOP) elevation. The cannabinoid, noladin ether, was found to have no effect on outflow facility. An advanced glycation endproduct cross-link breaker, which was found to produce glaucomatous plaques in vivo, was perfused through organ-culture anterior segments with no effect on IOP. Morphological analysis is forthcoming.This research used WNPRC Research Services.
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