Genetic dissection of pigmentary glaucoma

色素性青光眼的基因解析

• 批准号: 8630603
• 负责人: Michael G Anderson
• 金额: $ 30.09万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630603
• 关键词: Affect; Alleles; American; Animal Model; Animals; Blindness; Clinical; Collection; Data; Detection; Development; Disease; Dissection; Enrollment; Event; Eye; Family; Family Study; Functional disorder; Genes; Genetic; Genotype; Glaucoma; Goals; Human; Human Genetics; Incidental Findings; Individual; Inherited; Lead; Link; Melanins; Molecular; Molecular Analysis; Mus; Mutation; Mutation Analysis; Open-Angle Glaucoma; Outcome; Pathway interactions; Patients; Pharmacologic Substance; Physiologic Intraocular Pressure; Physiological; Pigments; Population; Prevalence; Productivity; Quality of life; Recording of previous events; Research; Resources; Risk Factors; Secondary to; Sequence Analysis; Shapes; Testing; Therapeutic; Trabecular meshwork structure; Treatment Factor; Variant; Vision; Visual; anterior chamber; casein kinase II; clinical practice; cohort; disability; disease-causing mutation; disorder risk; empowered; exome sequencing; genetic linkage analysis; genetic pedigree; genetic resource; high intraocular pressure; improved; insight; mouse model; patient population; pigment dispersion syndrome; public health relevance; research study; response

SUMMARY: Glaucoma is a leading cause of irreversible blindness and visual disability that has a major impact on the quality of life and productivity of millions of Americans. With no new pharmaceutical classes for treating glaucoma introduced into clinical practice since the 1990s, there remains a continuing need for improved regimes that treat glaucoma more effectively. Our long-term goal is to contribute to the development of these improved therapies by utilizing synergistic genetic approaches with mice and humans. Here, we focus on a sub-type of glaucoma, pigmentary glaucoma, and its major risk factor, pigment dispersion syndrome. Pigment dispersion is an alarmingly common condition characterized by aberrant release and collection of pigment throughout the anterior chamber of the eye. In most people, pigment dispersion causes no significant problems. However, in others, pigment dispersion leads to elevated intraocular pressure and pigmentary glaucoma. The factors initiating pigment dispersion and determining these very different potential outcomes are largely unknown. Our central hypothesis is that dispersed pigment elicits active, modifiable, physiological responses by the trabecular meshwork that are shaped by genetics and that dictate whether or not the insult progresses to secondary glaucoma. Using human genetics, we are studying families affected by pigment dispersion to identify genetic factors causing initiation of pigment dispersion. Using approaches with mice, we have developed an inducible mouse model for studying physiological responses to pigment dispersion and identified genetic suppressors of pigmentary glaucoma for studying potential treatments. Our objective in this proposal is to utilize and build on these resources to study molecular events contributing to pigment dispersion and its conversion to pigmentary glaucoma. To accomplish this, we propose: (SA1) to identify genes linked with pigmentary glaucoma using human genetics, (SA2) to define predictors of ocular responses to pigment dispersion using inducible mouse models, and (SA3) to identify suppressors of pigmentary glaucoma using mouse models.

概括： 青光眼是不可逆转的失明和视觉障碍的主要原因，对 数百万美国人的生活质量和生产力。没有新的药物治疗 青光眼自1990年代以来一直引入临床实践中，仍在不断改善 更有效地治疗青光眼的方案。我们的长期目标是为这些发展做出贡献 通过利用小鼠和人类的协同遗传方法来改善疗法。在这里，我们专注于 青光眼，色素青光眼及其主要危险因素（色素分散综合征）的亚型。颜料 色散是一种令人震惊的常见状况，其特征是异常释放和收集色素 在整个眼睛的前室。在大多数人中，色素色散不会引起任何重大意义 问题。但是，在其他情况下，色素色散会导致眼内压力升高和色素 青光眼。启动色素分散并确定这些截然不同的潜在结果的因素 在很大程度上未知。我们的中心假设是分散的色素会引起活动，可修改，生理 小梁网的反应是由遗传学塑造的，并决定侮辱是否决定 发展为继发青光眼。使用人类遗传学，我们正在研究受颜料影响的家庭 分散体以鉴定导致色素分散剂引发的遗传因素。使用小鼠的方法，我们 已经开发了一种可诱导的小鼠模型，用于研究对色素分散体的生理反应和 鉴定出用于研究潜在治疗的色素青光眼的遗传抑制剂。我们的目标 建议是利用并以这些资源为基础来研究有助于色素分散的分子事件 及其转化为色素青光眼。为了实现这一目标，我们建议：（SA1）识别链接的基因 使用人类遗传学的色素青光眼，（SA2）定义了眼睛对色素反应的预测指标 使用可诱导小鼠模型的分散和（SA3）使用色素青光眼的抑制剂使用 鼠标模型。