Genetic dissection of pigmentary glaucoma

描述（由申请人提供）：青光眼是不可逆失明和视力障碍的主要原因，对数百万美国人的生活质量和生产力产生重大影响。自20世纪90年代以来，没有新的治疗青光眼的药物类别被引入临床实践，因此仍然需要改进更有效治疗青光眼的制度。我们的长期目标是通过对小鼠和人类使用协同遗传方法来促进这些改进疗法的发展。在这里，我们关注青光眼的一种亚型——色素性青光眼及其主要危险因素——色素分散综合征。色素分散是一种非常常见的情况，其特征是色素在整个眼睛前房的异常释放和收集。对大多数人来说，色素分散不会引起严重的问题。然而，在其他情况下，色素分散导致眼压升高和色素性青光眼。引发色素分散和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，分散的色素引起了小梁网活跃的、可改变的生理反应，这种反应是由遗传决定的，并决定了这种损伤是否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分散影响的家族，以确定引起起始的遗传因素

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.