Factors Determining Intraocular Pressure and Glaucoma Susceptibility

描述(由申请人提供)：我们的目标是识别和表征导致高眼压和青光眼的新基因、途径和分子机制。这是合理改善患者护理的关键一步。眼压升高是青光眼的主要危险因素。眼压升高和青光眼的机制在很大程度上还不清楚。我们用人类和小鼠来研究青光眼的遗传学。利用小鼠发现青光眼途径是一种重要的方法，因为小鼠在实验上很容易驯化，而且仍然很难在患者群体中识别许多青光眼基因。(目的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识别诱导眼压升高的新基因和机制。我们将对所涉及的遗传途径进行表征，并对其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识别基因的人类同源基因。(目的2)有效突变体的有限可用性仍然是阻碍利用小鼠发现青光眼基因的主要因素。因此，我们将进行表型驱动的突变筛选，以确定与眼压升高和青光眼相关的新基因和分子机制。我们建议对青光眼突变进行敏化ENU筛查。我们将以各种方式使屏幕变得敏感，包括一种人类基因在老鼠身上的同源突变，这种突变使人们容易患上高眼压和青光眼，我们在老鼠身上重复了这种倾向。为了加速青光眼相关基因和机制的发现，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突变筛查的力量，同时结合我们在确定疾病机制和检查眼睛表型方面的成熟经验，将使我们能够识别和表征导致高眼压和青光眼的新基因和分子过程。新的突变体将有巨大的潜力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.