This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Objective: 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 determine the effects of proprietary compounds on in vitro CM contraction/relaxation. To determine whether the stable endocannabinoid, noladin ether, which has been shown increase outflow facility in pig organ-cultured anterior segments, has the same effect on outflow facility in monkey organ-cultured anterior segments. 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. Progress: 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. A proprietary ion channel modulating compound relaxes carbachol precontracted and resting CM. This class of compounds may potentially be developed as glaucoma therapeutics. The stable endocannabinoid, noladin ether, had no effect on outflow facility in monkey organ-cultured anterior segments. Noladin ether did alter the actin cytoskeleton in proliferating but not quiescent human trabecular meshwork cells in vitro. These results suggest species specific effects of noladin ether since it was effective in altering outflow facility and the actin cytoskeleton in pig organ culture and trabecular meshwork cells respectively. 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 which block the interaction of cellular adhesions with the surrounded extracellular matrix enhance trabecular outflow. Overexpression of the protein cochlin, which is elevated only in human glaucoma, increases intraocular pressure (IOP) and decreases trabecular outflow. This research used WNPRC Research Services.
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