Sex differences in in vitro and in vivo glaucoma models may predict gender specific dose adjustment needs

体外和体内青光眼模型的性别差异可以预测性别特异性剂量调整需求

• 批准号: 10333877
• 负责人: Suchismita Acharya
• 金额: $ 14.77万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10333877
• 关键词: Affect; Animals; Antioxidants; Aqueous Humor; Aromatase; Blood Circulation; Catechol O-Methyltransferase; Cells; Cessation of life; Characteristics; Ciliary Body; Collagen; Crush Injury; Cytoprotection; Disease; Dose; Endothelium; Enzymes; Epidemiology; Estradiol; Estrogen Receptors; Estrogens; Experimental Models; Extracellular Matrix; Eye; Eyedrops; Female; Gender; Gene Expression; Glaucoma; Goals; Human; Hybrids; Hypoxia; In Vitro; Incidence; Laboratories; Metalloproteases; Modeling; Molecular; Mus; Muscle Tonus; Nerve Crush; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Ocular Hypertension; Optic Nerve; Oxidative Stress; Pharmaceutical Preparations; Physiologic Intraocular Pressure; Plasminogen; Postmenopause; Primary Open Angle Glaucoma; Procedures; Production; Prostaglandin D2; Publishing; Rattus; Regulation; Retina; Retinal Ganglion Cells; Rodent Model; Sex Differences; Signal Pathway; Signal Transduction; Smooth Muscle; Superoxide Dismutase; Suspensions; System; TXNIP gene; Testing; Therapeutic Index; Tissues; Trabecular meshwork structure; United States; United States National Institutes of Health; Vascular resistance; Woman; Women' s Group; analog; animal tissue; antiglaucoma drug; antioxidant enzyme; base; connective tissue growth factor; design; epidemiology study; gender difference; heme oxygenase-1; human male; in vivo; male; men; mimetics; mouse model; nanoencapsulated; novel; novel therapeutics; personalized medicine; pressure; response; sex; targeted treatment

PROJECT SUMMARY One of the most definite epidemiological characteristics of primary open angle glaucoma (POAG) is that, its incidence shows a strong sex-related difference. Nitric oxide (NO) is directly implicated in the regulation of intraocular pressure (IOP) in glaucoma. Our laboratory is currently working on design, synthesis and testing of a novel hybrid class of NO donors to lower IOP with neuroprotective activity in rodent models. Several epidemiological studies have suggested that estrogen levels correlate positively to increased retinal blood circulation, increased NO synthesis and negatively with intra ocular pressure (IOP) levels. Estrogen increases the activity of endothelial-based nitric oxide synthase (NOS) and therefore regulates smooth muscle tone and vascular resistance. Since estrogen receptors are located in the trabecular meshwork, ciliary body and the outflow system of the eye, it might potentially influence IOP by regulating both aqueous humor production and outflow. Consequently, there may be gender-dependent differential response to anti-glaucoma drugs especially to that simultaneously deliver NO along with antioxidant activity which interfere with estrogen signaling in men and women. The goal of this project is to determine the gender specific effects of the NO donating- antioxidant hybrid compounds on the trabecular meshwork (TM) cell’s anti-oxidant enzyme status, extracellular matrix composition, estrogen regulating enzyme levels and on the overall IOP lowering activity. We have synthesized a novel multifunctional hybrid anti-oxidant and NO donating compound SA-2 as well as several other novel highly antioxidant derivatives of SA-2 compound. Our published results ensued from this project demonstrated that a single eye drop of a nano encapsulated suspension of SA-2 lowered IOP by 50% in mouse as well as in rat glaucoma model (in both males and females). Additionally, compound SA-2 is neuroprotective ex vivo in hypoxia treated retinal explants and in the in vivo IOP-independent optic nerve crush (ONC) model performed in female mice. In our preliminary result using human trabecular meshwork (hTM) cells, we found that there is a gender dependent difference in the cytoprotective activity of SA-2 at 1mM dose. We further found that, the female mice respond differently than male mice when subjected to ONC injury. Specifically, for this NIH supplement application, we propose to use primary human hTM cell derived both from female and male donors (specific aim 1) as well as in glaucomatous TM tissues from three animal groups: females, males and ovariectomized (OVX) females, in which OVX procedure models a postmenopausal state (specific aim 2). We hypothesize that, compound SA-2 and its novel analog SA-10 will have differential cellular and molecular activities depending on the gender and estrogen-related signaling. Successful completion of the proposed studies will have an implication for developing novel therapeutics for glaucoma with emphasis to a gender differences to help design more personalized therapies along with gender specific dose adjustment.

项目概要 原发性开角型青光眼（POAG）最明确的流行病学特征之一是，其 发病率显示出强烈的性别相关差异，一氧化氮（NO）直接参与调节。 我们的实验室目前正致力于青光眼眼压（IOP）的设计、合成和测试。 一种新型混合型 NO 供体，可在啮齿动物模型中降低眼压并具有神经保护活性。 流行病学研究表明，雌激素水平与视网膜血流量增加呈正相关 循环，NO 合成增加，并与眼内压 (IOP) 水平增加产生负面影响。 内皮型一氧化氮合酶 (NOS) 的活性，从而调节平滑肌张力和 由于雌激素受体位于小梁网、睫状体和血管阻力。 眼睛的流出系统，它可能通过调节房水的产生和 经测试，抗青光眼药物可能存在性别依赖性差异反应。 同时提供一氧化氮和抗氧化活性，干扰男性雌激素信号传导 该项目的目标是确定 NO 捐赠对性别的特定影响。 抗氧化杂合化合物对小梁网（TM）细胞抗氧化酶状态的影响， 细胞外基质组成、雌激素调节酶水平和整体眼压降低 活动。 我们合成了一种新型多功能杂化抗氧化剂和NO供给化合物SA-2以及 我们发表的结果是由此产生的 SA-2 化合物的其他几种新型高抗氧化衍生物。 项目证明，SA-2 纳米胶囊悬浮液的单滴眼药水可将眼压降低 50% 此外，化合物 SA-2 在小鼠和大鼠青光眼模型中均有效。 在缺氧处理的视网膜外植体和体内不依赖眼压的视神经挤压中具有离体神经保护作用 在我们使用人类小梁网（hTM）细胞进行的（ONC）模型中， 我们发现 1mM 剂量的 SA-2 的细胞保护活性存在性别依赖性差异。 进一步发现，当受到 ONC 损伤时，雌性小鼠的反应与雄性小鼠不同。 具体来说，对于此 NIH 补充应用，我们建议使用源自以下来源的原代人类 hTM 细胞： 女性和男性供体（具体目标 1）以及来自三个动物组的青光眼 TM 组织： 女性、男性和卵巢切除 (OVX) 女性，其中 OVX 程序模拟绝经后状态 （具体目标2）我们勇敢地说，化合物SA-2及其类似物新型SA-10将具有差异性细胞。 和分子活动取决于性别和雌激素相关信号的成功完成。 拟议的研究将对开发青光眼治疗小说产生影响，重点是 性别差异有助于设计更个性化的疗法以及针对特定性别的剂量调整。