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.Nitric oxide (NO) donors such as SNP and ISDN were most effective in relaxing precontracted CM in vitro. The non-selective NO synthase inhibitor L-NAME induced further contraction, possibly suggesting some endogenous production of NO in the longitudinal CM. Signaling pathways utilized to induce the relaxation are being determined. 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 was established. Enhancement or trabecular outflow was demonstrated in response to H-7, a compound know to increase trabecular outflow in vivo. Viral vectors containing two different genes that alter the actin cytoskeleton were also found to be effective in increasing outflow facility in this system by targeting the trabecular meshwork outflow pathway. This gene therapy approach for the anterior segment has the potential to 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. This research used WNPRC Research Services.
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