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。 高眼压（IOP）是青光眼的主要危险因素。我们 目的是识别和表征有助于 眼压升高和青光眼具体来说，我们用老鼠作为模型 进行表型驱动诱变筛选以鉴定新的 青光眼发病机制和途径。的力量 表型驱动的诱变筛选是不需要先验的 有关因素或途径的信息。由于目前所知甚少 关于IOP稳态，这种鉴定新遗传因子的方法是 理想.我们建议，在这笔赠款的时间，我们将确定大约 10种新的青光眼相关突变。这种方法已经为我们提供了一个 我们建议克隆一个原发性先天性青光眼的新位点（Eel）， 第二个放大的眼睛突变体（Ee3），我们将表征和精细映射。一 我们的表型驱动筛选的特点是富集突变检测， 小鼠5号染色体，在与人染色体7q36的保守同线性区域中。 该区域包含2个人类青光眼基因座，其遗传原因是 未知虽然我们能够为这一具有相当重要意义的地区提供丰富的资源， 我们的方法并不妨碍在其他地方识别突变的可能性。 基因组因此，有助于IOP的突变将被定位， 基于与人类肿瘤表型的相似性和已知的 人类青光眼地图位置。我们预测，利用表型的力量 驱动的诱变筛选与我们独特的工具并行， 我们将能够识别和表征新的遗传因素 有助于提高IOP和促进对青光眼的了解。

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 identify and characterize genetic factors that contribute to elevated IOP and glaucoma. Specifically, 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 phenotype driven mutagenesis screen is that there is no requisite a priori information for factors or pathways involved. Since little is currently known about IOP homeostasis, this method for identification of new genetic factors is ideal. We propose that in the time of this grant we will identify approximately 10 new glaucoma related mutations. This method has already provided us with one new locus (Eel) for primary congenital glaucoma that we propose to clone and a second enlarged eye mutant (Ee3) that we will characterize and fine map. A feature of our phenotype-driven screen is enrichment for mutation detection on mouse chromosome 5, in a region of conserved synteny to human chromosome 7q36. This region contains 2 human glaucoma loci for which the genetic cause is unknown. While we are able to enrich for this region of considerable interest, our method does not impede the likelihood of identifying mutations elsewhere in the genome. Therefore, mutations contributing to IOP and will be mapped and prioritized based on similarity to human glaucomatous phenotypes and known human glaucoma map positions. We predict that using the power of a phenotype driven mutagenesis screen in parallel with our unique tools to examine ocular phenotypes we will be able to identify and characterize new genetic factors that contribute to elevated IOP and advance understanding of glaucoma.