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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

基本信息

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
项目类别：
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&apos 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

项目摘要

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