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.

项目总结 原发性开角型青光眼最明确的流行病学特征之一是，其 发病率显示出与性别有关的强烈差异。一氧化氮(NO)直接参与血管紧张素转换酶的调节。 青光眼患者的眼压。我们的实验室目前正在致力于设计、合成和测试 一种新的具有神经保护活性的混合类NO供体降低啮齿动物模型的眼压。几个 流行病学研究表明，雌激素水平与视网膜血液增加呈正相关。 循环、NO合成增加，与眼压水平呈负相关。雌激素增加 以内皮细胞为基础的一氧化氮合酶(NOS)的活性，从而调节平滑肌张力和 血管阻力。由于雌激素受体位于小梁网、睫状体和 眼部流出系统，可能通过调节房水生成和眼压而潜在地影响眼压 外流。因此，对抗青光眼药物的反应可能因性别而异。 同时产生一氧化氮和抗氧化剂活性，从而干扰男性体内的雌激素信号 还有女人。这个项目的目标是确定不捐献的性别影响- 抗氧化杂化化合物对小梁网络(TM)细胞抗氧化酶状态的影响， 细胞外基质组成、雌激素调节酶水平与整体眼压下降 活动。 我们合成了一种新型多功能杂化抗氧剂和NO供体化合物SA-2以及 其他几种新的SA-2化合物的高抗氧化性衍生物。我们发表的结果就是由此而来的 项目显示，一滴纳米胶囊SA-2混悬液的单眼滴眼液可使患者的眼压降低50% 小鼠青光眼模型和大鼠青光眼模型(雄性和雌性)。此外，化合物SA-2是 低氧处理视网膜移植物和非眼压非依赖性视神经损伤的体外神经保护作用 (ONC)雌性小鼠模型。在我们使用人类小梁网络(HTM)细胞的初步结果中， 我们发现SA-2在1 mM剂量下的细胞保护活性存在性别差异。我们 进一步发现，雌性小鼠在受到ONC损伤时的反应与雄性小鼠不同。 具体地说，对于这个NIH补充剂应用，我们建议使用来源于 女性和男性供体(特定目标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)。我们推测，化合物SA-2及其新的类似物SA-10将具有差异细胞 分子活性取决于性别和雌激素相关信号。圆满完成 拟议的研究将对开发青光眼的新疗法具有重要意义，重点是 性别差异，以帮助设计更个性化的治疗，以及性别特定的剂量调整。