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.

项目摘要 主要开放角度青光眼（POAG）最定义的流行病学特征之一是，它 发病率显示与性别有关的差异很强。一氧化氮（NO）直接与调节有关 眼内压（IOP）中的青光眼。我们的实验室目前正在研究设计，合成和测试 啮齿动物模型中具有神经保护活性的降低IOP的新型杂种类别的无供体。一些 流行病学研究表明，雌激素水平与残留血液呈正相关 循环，无合成的增加，并且具有眼内压力（IOP）水平。雌激素增加 基于内皮的一氧化氮合酶（NOS）的活性，因此调节平滑肌张力和 血管抗性。由于雌激素受体位于小梁网，睫状体和 眼睛的出口系统，它可能通过控制水性幽默的产生和 外流。因此，尤其是对抗云可瘤药物的性别依赖性差异反应 为此，仅提供没有抗氧化活性的抗氧化活性，从而干扰男性的雌激素信号 和女人。该项目的目的是确定无捐赠的性别特定效应 - 小梁网（TM）细胞的抗氧化酶状态上的抗氧化剂杂交化合物， 细胞外基质组成，雌激素调节酶水平以及总体IOP降低 活动。 我们已经合成了一种新型的多功能杂化抗氧化剂，没有捐赠化合物SA-2以及 SA-2化合物的其他几种新型高度抗氧化剂衍生物。从中获得了我们发布的结果 项目表明，一只纳米封装的SA-2悬架单滴使IOP降低了50％ 小鼠以及大鼠青光眼模型（在男性和女性中）。此外，复合sa-2是 缺氧治疗的永久性外植体和体内IOP独立的视神经挤压的神经保护症 （ONC）在雌性小鼠中进行的模型。在我们的初步结果中，使用人类小梁网（HTM）细胞， 我们发现，在1mm剂量下SA-2的细胞保护活性存在性别依赖性差异。我们 进一步发现，雌性小鼠在遭受ONC损伤时的反应与雄性小鼠的反应不同。 具体而言，对于这种NIH补充剂，我们建议使用均来自 女性和男性捐助者（特定目标1）以及来自三个动物群的青光眼TM组织： 女性，雄性和卵巢切除（OVX）女性，其中OVX手术对绝经后状态进行建模 （特定目标2）。我们假设，化合物SA-2及其新颖的模拟SA-10将具有不同的细胞 以及分子活性取决于性别和与雌激素相关的信号传导。成功完成 拟议的研究将对开发青光眼的新疗法有意义，重点是 性别差异有助于设计更多个性化疗法以及特定性别剂量调整。