Factors Determining Intraocular Pressure

描述（由申请人提供）：青光眼是导致失明的主要原因。眼内压（IOP）升高是青光眼的主要危险因素。我们的目标是继续识别和表征导致IOP升高和青光眼的遗传因素。我们使用小鼠作为模型系统进行表型驱动的诱变筛选，以确定青光眼发病机制中涉及的新机制和途径。表型驱动筛选的力量在于，对于所涉及的因子或途径没有必要的先验信息。在我们之前的资助期间，我们已经确定了一些青光眼相关的小鼠突变体（Grms），这些突变体显示出青光眼的特征，包括高IOP、视网膜神经节细胞死亡和视神经萎缩。在这个提议中，我们将确定我们已经开始研究的几个与肿瘤相关的突变体中的致病突变。我们将描述所涉及的遗传途径，并对发病机制进行更详细的调查。青光眼的小鼠模型非常少，我们的突变体将是有价值的模型，了解人类青光眼和促进人类突变的鉴定。由于可用的突变体数量少，严重限制了小鼠青光眼研究，我们提出了一种新的CYP 1B 1致敏的END筛查显性青光眼突变。许多报道的人类青光眼位点具有显性效应。人类CYP 1B 1基因突变使人易患高眼压和青光眼，我们在小鼠中重复了这种易感性。我们将筛选1000 G1男性/年的IOP升高和其他眼部异常，十倍以上的家庭比可能在以前的授予期。我们预计生产15-40青光眼相关的突变体，将提供给青光眼社区尽快是可行的。我们相信，继续使用表型驱动的诱变筛选的能力，同时使用我们独特的工具来检查眼部表型，将使我们能够识别和表征导致IOP升高和青光眼的新遗传因素。新的突变体有很大的潜力来改变我们对青光眼的理解。与公共卫生的相关性：青光眼是导致失明的主要原因之一。人类基因组的20多个区域与青光眼有关，但很少有基因被鉴定出来。我们的建议旨在产生人类青光眼的小鼠模型，作为了解青光眼机制的工具，以帮助识别人类青光眼基因和测试新的治疗方法。

DESCRIPTION (provided by applicant): Glaucoma is a leading cause of blindness. Elevated intraocular pressure (IOP) is a major risk factor for glaucoma. Our goal is to continue to identify and characterize genetic factors that contribute to elevated IOP and glaucoma. We are using the mouse as a model system to conduct a phenotype driven mutagenesis screen to identify novel mechanisms and pathways involved in glaucoma pathogenesis. The power of a phenotype driven screen is that there is no requisite, a priori information for factors or pathways involved. In our previous funding period, we have identified a number of glaucoma relevant mouse mutants (Grms) that show hallmarks of glaucoma including high IOP, retinal ganglion cell death and optic nerve atrophy. In this proposal, we will identify the causative mutations in a few of these glaucoma-relevant mutants that we have started to study. We will characterize the genetic pathways involved and carry out more detailed investigations into the pathogenesis. Very few mouse models of glaucoma exist and our mutants will be valuable both as models for understanding human glaucoma and for facilitating the identification of human mutations. Since the small number of available mutants severely limits mouse studies of glaucoma, we propose a new Cyp 1b1 -sensitized END screen for dominant glaucoma mutations. A number of reported human glaucoma loci have a dominant effect. Mutations in the human CYP1B1 gene predispose people to high IOP and glaucoma, a predisposition we have repeated in mice. We will screen 1000 G1 males/year for IOP elevation and other ocular abnormalities, ten times more families than was possible in the previous granting period. We anticipate producing 15-40 glaucoma- relevant mutants that will be made available to the glaucoma community as quickly as is feasible. We are confident that continuing to use the power of a phenotype-driven mutagenesis screen in parallel with our unique tools to examine ocular phenotypes will enable us to identify and characterize new genetic factors that contribute to elevated IOP and glaucoma. The new mutants have great potential to transform our understanding of glaucoma. Relevance to Public Health: Glaucoma is one of the leading causes of blindness. Over 20 regions of the human genome have been implicated in glaucoma but very few genes have been identified. Our proposal aims to produce mouse models of human glaucoma to be used as tools to understand the mechanisms of glaucoma, to help identify human glaucoma genes and to test new treatments.