GLAUCOMA THERAPY, CILIARY MUSCLE CONTRACTION AND TRABECULAR OUTFLOW

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：研究产生一氧化氮(NO)的化合物对体外收缩或静息的睫状肌(CM)是否具有松弛作用。这是一种指标，表明这类化合物作为降低青光眼眼内压的一种方法，是否有助于促进葡萄膜巩膜流出。目的：研究中成药对体外心肌收缩/松弛的影响。为了确定稳定的内源性大麻素诺拉丁醚是否增加了猪器官培养前节段的流出便利性，是否也对猴子器官培养的前节流出便利性有相同的影响。利用器官培养中的猴眼前节细胞，研究基因治疗和其他分子对小梁流出的影响，这可能对青光眼的治疗也有重要意义。 进展：用于诱导对一氧化氮供体的CM松弛反应的信号通路正在确定中。在给予一氧化氮供体之前，用鸟苷环化酶途径的抑制剂ODQ进行预处理的效果目前正在调查中。在CM松弛(没有供体)或收缩(可能没有合成酶抑制剂)的治疗领域，没有化合物具有潜在的价值，例如在青光眼的治疗中。 一种专有的离子通道调节化合物可以松弛预先收缩和静息的CM。这类化合物可能被开发为治疗青光眼的药物。 稳定的内源性大麻素诺拉丁醚对猴器官培养前节段的流出功能无影响。诺拉丁醚确实改变了体外增殖但不静止的人眼小梁细胞的肌动蛋白细胞骨架。这些结果提示，诺拉丁醚对猪器官培养和小梁网细胞的流出设施和肌动蛋白细胞骨架的影响具有物种特异性。 猴子器官培养的眼前段系统正被用来确定药物治疗和基因治疗对小梁流出的影响，这可能随后被用于青光眼治疗以降低眼压。来自纤维连接蛋白肝素II结构域的多肽可以阻断细胞黏附与周围细胞外基质的相互作用，促进小梁流出。Cochlin蛋白的过度表达只在人类青光眼中升高，会增加眼压(IOP)并减少小梁流出。 这项研究使用了WNPRC Research Services。

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.