Genetic dissection of pigmentary glaucoma

色素性青光眼的基因解析

• 批准号: 8798658
• 负责人: Michael G Anderson
• 金额: $ 29.49万
• 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/8798658
• 关键词: Affect; Alleles; American; Animal Model; Animals; Blindness; Clinical; Collection; Data; Detection; Development; Disease; Dissection; Enrollment; Event; Eye; Family; Functional disorder; Genes; Genetic; Genetic study; Genotype; Glaucoma; Goals; Health; Human; Human Genetics; Incidental Findings; Individual; Inherited; Lead; Link; Melanins; Molecular; Molecular Analysis; Mus; Mutation; Mutation Analysis; Outcome; Pathway interactions; Patients; Pharmacologic Substance; Physiologic Intraocular Pressure; Physiological; Pigmentary Glaucoma; 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 approach; genetic linkage analysis; genetic pedigree; genetic resource; high intraocular pressure; improved; insight; mouse model; patient population; pigment dispersion syndrome; research study; response

DESCRIPTION (provided by applicant): 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 o 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.

描述（由申请人提供）：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O美国人的生活质量和生产率产生了重大影响。自1990年代以来，由于没有新的用于治疗青光眼的药物治疗青光眼的药物类别，因此仍然需要改善更有效治疗青光眼的状态。我们的长期目标是通过利用与小鼠和人类的协同遗传方法来为这些改进的疗法的发展做出贡献。在这里，我们专注于青光眼，色素青光眼的亚型及其主要危险因素，色素分散综合征。颜料分散是一种令人震惊的常见状况，其特征是整个眼前室内的异常释放和色素收集。在大多数人中，色素色散不会引起重大问题。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。引发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尚不清楚。我们的中心假设是，分散的颜料会通过小梁网状作品产生活跃，可修改的生理反应，这些反应是由遗传学塑造的，这决定了损害是否发展为继发性glaucoma。使用人类遗传学，我们正在研究受色素分散影响的家庭，以鉴定引起起始的遗传因素 色素分散。使用小鼠的方法，我们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，并确定了用于研究潜在治疗的色素青光眼的遗传抑制剂。我们在这项建议中的目标是利用并建立这些资源来研究有助于色素分散剂及其转化为色素青光眼的分子事件。为此，我们提出：（SA1）使用人遗传学识别与色素青光眼相关的基因，（SA2），以使用诱导小鼠模型来定义眼部对色素分散体的反应预测指标，（SA3）使用小鼠识别小鼠的抑制剂型号。