Gene-Environment Interactions in Glaucoma

青光眼的基因与环境相互作用

基本信息

批准号：
8830454
负责人：
Louis Robert Pasquale
金额：
$ 44.6万
依托单位：
MASSACHUSETTS EYE AND EAR INFIRMARY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8830454
关键词：
Age Aging Anthocyanins Berry Bioflavonoid Biological Markers Blindness CAV1 gene CAV2 gene Caveolins Cell membrane Cell physiology Clinical Clinical Trials Code Cohort Analysis Collaborations Communication Complex Data Databases Diet Dietary Flavonoid Disease Drug Targeting ESR1 gene ESR2 gene Endothelial Cells Environmental Risk Factor Estradiol Estrogen Metabolism Estrogen Receptors Estrogens Estrone Flavonoids Food Functional disorder GUCY1A3 gene GUCY1B3 gene Genetic Genetic Markers Genetic Predisposition to Disease Genetic Risk Genotype Glaucoma Goals Gonadal Steroid Hormones Health Professional Hormone use Human Genetics Hypertension Intake Internet Lead Mediating Menopause Metabolic Pathway Metabolism Modeling National Eye Institute Nitric Oxide Nitric Oxide Synthase Non-Insulin-Dependent Diabetes Mellitus Nurses&apos Health Study Optic Nerve Pathology Patients Peripheral Physiologic Intraocular Pressure Postmenopause Prevention strategy Preventive Intervention Primary Open Angle Glaucoma Primary Prevention Publishing Resources Retinal Retinal Ganglion Cells Risk Serum Signal Transduction Smoking Smooth Muscle Time Trabecular meshwork structure Translating Variant Vision Visual Fields Woman Work base case control cost effective endophenotype endothelial dysfunction experience follow-up gene environment interaction genetic variant human NOS3 protein improved men novel optic nerve disorder prospective public health relevance

项目摘要

DESCRIPTION (provided by applicant): Primary open-angle glaucoma (POAG) is an intraocular pressure (IOP) - dependent, slowly progressive optic neuropathy that ultimately leads to blindness. Our prior work suggests that impaired nitric oxide (NO) signaling, exacerbated by declining estrogen levels contributes to dysfunctional endothelial cell - smooth muscle communication in POAG. In this proposal, using resources from the Nurses Health Study (NHS), we will compare circulating estrogen levels in postmenopausal women with and without POAG. Age at menopause has a genetic basis, and later age has been associated with reduced risk of POAG. Using data from the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (NEIGHBORHOOD), we will evaluate whether a genetic predisposition score related to age at menopause is associated with POAG. Finally, we will also assess whether specific genotypes in the estrogen metabolic pathway interact with serum estrogen levels in POAG. Our data indicate that genomic variants in CAV1/CAV2, which codes for caveolins juxtaposed to NO synthase 3 (NOS3) in endothelial cell membranes, are related to POAG. Statin use may modulate the functional interaction between caveolin and NO signaling in endothelial cells to favorably alter glaucoma risk. We will perform a prospective cohort analysis of the relation between current statin use and POAG in NHS, NHS2 and the Health Professionals Follow-up Study (HPFS). We will also evaluate whether statin use interacts with common variants of CAV1/CAV2 and NOS3 in POAG. We will extend our analysis of environmental factors related to endothelial cell function to dietary bioflavonoids, which are known to alter endothelial cell function. There is evidence that POAG patients with initial paracentral visual field loss have endothelial cell dysfunction, yet little is known regarding environmental determinants of paracentral visual field loss in POAG. We have discovered two genetic biomarkers of endothelial cell dysfunction in POAG patients with paracentral visual field loss: CAV1/CAV2, GUCY1A3 / GUCY1B3. We will assess if factors that alter endothelial cell function, such as hypertension and postmenopausal hormone use, are associated with this glaucoma endophenotype. POAG is disease with a complex web of pathology. This proposal draws on the wealth of biomarkers related to endothelial cell dysfunction and estrogen metabolism in NHS, NHSII, HPFS and the NEIGHBORHOOD to dis- entangle that web. The proposal aims to identify and develop more rational preventive strategies and interventions for POAG.

描述（由申请人提供）：主要的开角式青光眼（POAG）是眼内压（IOP） - 依赖性，缓慢进行性视神经病变，最终导致失明。我们先前的工作表明，一氧化氮（NO）信号传导受损，雌激素水平下降会加剧雌激素水平的促进功能障碍的内皮细胞 - POAG中的平滑肌通信。在此提案中，使用护士健康研究（NHS）的资源，我们将比较有或没有POAG的绝经后妇女的雌激素水平。更年期的年龄具有遗传基础，后来的年龄与POAG风险降低有关。使用国家眼研究所青光眼人类遗传学合作的数据，可遗传的总体操作数据库（邻域），我们将评估与POAG相关的遗传性倾向得分是否与POAG相关。最后，我们还将评估雌激素代谢途径中的特定基因型是否与POAG中血清雌激素水平相互作用。我们的数据表明，CAV1/CAV2中的基因组变体与内皮细胞膜中无合酶3（NOS3）并列的小窝蛋白编码与POAG有关。他汀类药物的使用可能调节内皮细胞中小窝蛋白和无信号传导之间的功能相互作用，以有利地改变青光眼风险。我们将对NHS，NHS2与卫生专业人员随访研究（HPFS）中当前他汀类药物使用与POAG之间的关系进行前瞻性队列分析。我们还将评估他汀类药物的使用是否与POAG中CAV1/CAV2和NOS3的常见变体相互作用。我们将把与内皮细胞功能相关的环境因素的分析扩展到饮食生物类黄酮，这些生物类黄酮已知会改变内皮细胞功能。有证据表明，具有最初的上腹视野损失的POAG患者具有内皮细胞功能障碍，但对于POAG中上心视野损失的环境决定因素知之甚少。我们已经发现了具有外腹视野损失的POAG患者的内皮细胞功能障碍的两个遗传生物标志物：CAV1 / CAV2，GUCY1A3 / GUCY1B3。我们将评估改变内皮细胞功能的因素（例如高血压和绝经后激素的使用）是否与这种青光眼型内型型有关。 POAG是疾病，具有复杂的病理网络。该建议借鉴了与内皮细胞功能障碍和NHS，NHSII，HPFS和邻里的内皮细胞功能障碍和雌激素代谢有关的丰富财富，以纠缠该网络。该提案旨在确定和制定POAG的更合理的预防策略和干预措施。