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.

总结： 青光眼是导致不可逆转的失明和视力残疾的主要原因，对人们的生活有着重大影响。 数百万美国人的生活质量和生产力。没有新的药物类别来治疗 青光眼自20世纪90年代引入临床实践以来，仍然持续需要改进的治疗方法。 治疗青光眼的方法。我们的长期目标是为这些领域的发展做出贡献。 通过利用小鼠和人类的协同遗传方法改进疗法。在这里，我们专注于 青光眼的亚型，色素性青光眼，及其主要危险因素，色素弥散综合征。颜料 分散是一种惊人的常见状况，其特征在于色素的异常释放和聚集 在眼睛的前房中。在大多数人中，色素分散不会引起显著的 问题然而，在其他情况下，色素分散导致眼内压升高和色素沉着。 青光眼引发色素分散并决定这些非常不同的潜在结果的因素 在很大程度上是未知的。我们的中心假设是，分散的色素具有活性，可改变的，生理的 小梁网的反应是由遗传形成的，决定了是否受到伤害， 发展为继发性青光眼。利用人类遗传学，我们正在研究受色素影响的家庭 分散，以确定遗传因素引起的色素分散的启动。使用小鼠的方法，我们 已经开发了一种用于研究对色素分散的生理反应的诱导型小鼠模型， 确定了色素性青光眼的遗传抑制因子，以研究潜在的治疗方法。我们的目标是 建议是利用和建立在这些资源上，研究有助于颜料分散的分子事件 并转变为色素性青光眼。为了实现这一点，我们建议：（SA1）确定基因连锁 使用人类遗传学研究色素性青光眼（SA2），以确定对色素的眼反应的预测因子 使用诱导型小鼠模型的分散，和（SA3）使用诱导型小鼠模型鉴定色素性青光眼的抑制剂。 小鼠模型。