Factors Determining Intraocular Pressure and Glaucoma Susceptibility

描述（由申请人提供）：我们的目标是鉴定和表征导致IOP升高和青光眼的新基因、途径和分子机制。这是合理改善患者护理的关键一步。眼内压升高伊萨青光眼的主要危险因素。IOP升高和青光眼的潜在机制在很大程度上尚未确定。我们使用人类和小鼠研究青光眼的遗传学。使用小鼠来发现青光眼通路是一种重要的方法，因为小鼠在实验上是易于处理的，并且仍然难以在患者群体中识别许多青光眼基因。 (Aim 1）我们将利用小鼠遗传学的力量，在我们已经发现并开始研究的新的青光眼相关突变体中鉴定诱导IOP升高的新基因和机制。我们将描述所涉及的遗传途径，并对分子发病机制进行更详细的研究。我们将合作评估人类患者中已鉴定基因的人类直系同源物。 (Aim 2）有用的突变体的有限可用性仍然是阻碍使用小鼠发现青光眼基因的主要因素。因此，我们将进行一个表型驱动的诱变筛选，以确定新的基因和分子机制参与眼压升高和青光眼。我们提出了一个敏感的ENU筛查青光眼突变。我们将以各种方式使筛选敏感，包括在小鼠中使人易患高眼压和青光眼的人类基因的直系同源物突变，我们在小鼠中重复了这种易感性。为了加速发现与肿瘤相关的基因和机制，我们将用最先进的测序和基因组方法来补充遗传学。继续使用表型驱动的诱变筛选的能力，与我们在确定疾病机制和检查眼部表型方面的成熟经验并行，将使我们能够鉴定和表征导致IOP升高和青光眼的新基因和分子过程。新的突变体将有很大的潜力来改变我们对青光眼的理解。

DESCRIPTION (provided by applicant): Our goal is to identify and characterize new genes, pathways and molecular mechanisms that contribute to elevated IOP and glaucoma. This is a critical step for rationally improving the care of patients. Elevated intraocular pressure (IOP) isa major risk factor for glaucoma. The mechanisms underlying IOP elevation and glaucoma are largely unidentified. We study the genetics of glaucoma using both the human and mouse. Using mice to discover glaucoma pathways is an important approach, as mice are experimentally tractable, and it remains difficult to identify many glaucoma genes in patient populations. (Aim 1) We will use the power of mouse genetics to identify novel genes and mechanisms that induce IOP elevation in new glaucoma-relevant mutants that we have discovered and started to study. We will characterize the genetic pathways involved and carry out more detailed investigations into the molecular pathogenesis. We will collaborate to assess the human orthologs of the identified genes in human patients. (Aim 2) The limited availability of useful mutants remains a major factor hindering glaucoma gene discovery using mice. Thus, we will conduct a phenotype driven mutagenesis screen to identify novel genes and molecular mechanisms involved in IOP elevation and glaucoma. We propose a sensitized ENU screen for glaucoma mutations. We will sensitize the screen in various ways including a mutation in the mouse ortholog of a human gene that predisposes people to high IOP and glaucoma, a predisposition that we have repeated in mice. To hasten the discovery of glaucoma-relevant genes and mechanisms, we will complement genetics with state-of-the-art sequencing and genomic approaches. Continuing to use the power of a phenotype-driven mutagenesis screen, in parallel with our proven experience in determining disease mechanisms and in examining ocular phenotypes, will enable us to identify and characterize new genes and molecular processes that contribute to elevated IOP and glaucoma. The new mutants will have great potential to transform our understanding of glaucoma.