Genetic dissection of pigmentary glaucoma

描述（由申请人提供）：青光眼是导致不可逆失明和视力残疾的主要原因，对数百万美国人的生活质量和生产力产生重大影响。由于自20世纪90年代以来没有新的用于治疗青光眼的药物类别引入临床实践，因此仍然持续需要更有效地治疗青光眼的改进方案。我们的长期目标是通过利用小鼠和人类的协同遗传方法来促进这些改进疗法的发展。在这里，我们集中在青光眼的一个亚型，色素性青光眼，其主要危险因素，色素弥散综合征。色素分散是一种惊人的常见病症，其特征在于色素在整个眼前房中的异常释放和聚集。在大多数人中，色素分散不会引起重大问题。然而，在其他情况下，色素分散导致眼内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，分散的色素通过遗传学形成的小梁网激发活跃的、可改变的生理反应，并决定损伤是否进展为继发性青光眼。利用人类遗传学，我们正在研究受色素分散影响的家庭，以确定导致启动的遗传因素 颜料分散体。使用小鼠的方法，我们已经开发了一种诱导型小鼠模型，用于研究对色素分散的生理反应，并确定了色素性青光眼的遗传抑制因子，用于研究潜在的治疗方法。我们的目标是利用和建立在这些资源的基础上，研究分子事件有助于色素分散及其转化为色素性青光眼。为了实现这一点，我们提出：（SA 1）使用人类遗传学来鉴定与色素性青光眼相关的基因，（SA 2）使用诱导型小鼠模型来定义对色素分散的眼部反应的预测因子，以及（SA 3）使用小鼠模型来鉴定色素性青光眼的抑制因子。

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.