Genetic dissection of pigment dispersing iris disease

描述（由申请人提供）：假性脱落综合征是一种常见的世界性年龄相关疾病，是开角型青光眼最常见的特异性病因。假性脱落综合征的发病机制几乎是完全未知的。目前，所有假剥脱性青光眼的治疗策略都以降低IOP为目标，并没有针对假剥脱综合征本身的特异性治疗方法。随着对启动机制的了解的增加，应该有可能设计出专门针对假性脱落综合征本身的改进的治疗策略，促进早期干预和改善医疗结果。我们的长期目标是通过利用小鼠和人类的协同遗传方法，为改进人类青光眼治疗的发展做出贡献。在这里，我们利用表型驱动的筛选方法在小鼠毛色变异中确定了一种新的眼病小鼠模型，该模型非常类似于假性脱落综合征的各个方面。我们在本提案中的目标是通过启动机制研究和完成菌株的表型表征来利用这一资源。利用小鼠遗传方法，我们正在测试眼睛对PEX综合征的易感性是通过影响细胞形态和与黑色素生成相关的氧化应激的机制介导的假设。怀疑同样的机制可能是人类PEX综合征的基础，我们同时进行人类遗传关联研究。这些研究的完成不仅将确定PEX综合征相关的遗传途径，而且还将开发出开发和测试未来治疗策略所需的动物模型。从长远来看，这些实验将有助于更好地了解青光眼，并最终改善人类治疗方法。假性脱落综合征是一种常见的年龄相关性疾病，是开角型青光眼最常见的病因。在这里，我们利用了一种新发现的小鼠模型，它非常类似于假性脱落综合征的各个方面。我们的目标是测试导致该小鼠品系表型的遗传途径，并测试这些基因在人类假脱落患者中的意义。

DESCRIPTION (provided by applicant): Pseudoexfoliation syndrome is a common age-related disease of worldwide significance and is the most commonly identified specific cause of open-angle glaucoma. The disease initiating mechanisms of pseudoexfoliation syndrome are almost completely unknown. Currently, all therapeutic strategies for pseudoexfoliative glaucoma aim to lower IOP and there are no specific therapies aimed at treating pseudoexfoliation syndrome itself. With increased knowledge of the initiating mechanisms, it should be possible to devise improved therapeutic strategies that specifically target pseudoexfoliation syndrome itself, promoting earlier interventions and improved medical outcomes. Our long-term goal is to contribute to the development of improved human glaucoma therapies by utilizing synergistic genetic approaches with mice and humans. Here, we take advantage of a phenotype-driven screening approach among mouse coat color variants that has identified a new mouse model of eye disease that strongly resembles aspects of pseudoexfoliation syndrome. Our objective in this proposal is to capitalize on this resource by initiating mechanistic studies and completing a phenotypic characterization of the strain. Using genetic approaches in mice, we are testing the hypothesis that susceptibility of the eye toward PEX syndrome is mediated via a mechanism influencing cellular morphology and oxidative stress associated with melanogenesis. Suspecting that the same mechanism likely underlies human PEX syndrome, we are simultaneously conducting human genetic association studies. Completion of these studies will not only identify PEX syndrome-related genetic pathways, but will also develop an animal model needed for development and testing of future therapeutic strategies. In the long-term, these experiments will contribute to a better understanding of glaucoma, and ultimately, to improved human therapies. Pseudoexfoliation syndrome is a common age-related disease of worldwide significance and is the most commonly identified specific cause of open-angle glaucoma. Here, we take advantage of a newly identified mouse model that strongly resembles aspects of pseudoexfoliation syndrome. Our objective in this proposal is to test the genetic pathways contributing to phenotypes of this mouse strain and test the significance of these genes among human pseudoexfoliation patients.