Factors Determining Intraocular Pressure

描述（由申请人提供）：青光眼是致盲的主要原因。眼压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。我们正在使用小鼠作为模型系统来进行表型驱动突变筛选，以确定青光眼发病机制的新机制和途径。表型驱动筛选的强大之处在于，没有必要的、先验的有关因素或途径的信息。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），它们表现出青光眼的特征，包括高IOP，视网膜神经节细胞死亡和视神经萎缩。在这个建议中，我们将确定一些我们已经开始研究的青光眼相关突变的致病突变。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研究。小鼠青光眼模型很少，我们的突变体将作为理解人类青光眼的模型和促进人类突变的识别。由于可用突变体数量少严重限制了青光眼的小鼠研究，我们提出了一种新的Cyp 1b1致敏的END筛选显性青光眼突变。许多已报道的人类青光眼基因座具有显性作用。人类CYP1B1基因的突变使人易患高眼压和青光眼，我们在小鼠身上重复了这种易感性。我们每年将筛查1000名G1男性的IOP升高和其他眼部异常，比之前的资助期可能多10倍。我们预计生产15-40个青光眼相关突变体，将尽快提供给青光眼社区。我们相信，继续使用表型驱动突变筛查的力量，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改变我们对青光眼的认识。与公共卫生相关：青光眼是致盲的主要原因之一。人类基因组中有超过20个区域与青光眼有关，但已确定的基因很少。我们的建议旨在建立人类青光眼的小鼠模型，作为了解青光眼机制的工具，帮助识别人类青光眼基因并测试新的治疗方法。

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.