Modulators for Retinal Ganglion Cell Injury

总结 青光眼是导致60岁以上美国人失明的主要原因。青光眼的一个危险因素是 中央角膜厚度角膜越薄，患青光眼的风险就越大。最近我们 已经确定了一种转录因子POU 6 F2，它调节小鼠中央角膜厚度， 是人类青光眼的危险因素。Pou 6 f2基因敲除小鼠的角膜比野生型更薄 同窝仔，而眼内压没有明显变化。我们认为POU 6 F2表达于 视网膜神经节细胞（RGC）的新亚类，其对青光眼损伤敏感。Previous：我们的四个 研究结果使我们假设POU 6 F2是一个转录级联反应，负责易感性， 一组新的ON-OFF定向选择性RGC亚型的早期死亡。为了验证这个假设，我们 将重点关注POU 6 F2在实验诱导和自然诱导模型中RGC反应中的作用- 发生青光眼。拟议的实验将揭示POU 6 F2分子级联，诱导 昏迷性损伤。我们将通过与Dr. Janey Wiggs和NEIGHBORHOOD联盟，询问NEIGHBORHOOD元数据集以定义 与POU 6 F2靶点相关的分子途径。我们将确定是否有任何这些下游目标， 它们的相关途径代表青光眼风险的因素。这种对分子的基本理解 POU 6 F2的相互作用将为合理设计策略提供信息，以改善POU 6 F2的检测和治疗。 青光眼

Summary The leading cause of blindness in Americans over the age of 60 is glaucoma. One risk factor for glaucoma is central corneal thickness. The thinner the cornea, the greater the risk of developing glaucoma. Recently, we have identified a transcription factor, POU6F2, that modulates central corneal thickness in the mouse and that is a risk factor for human glaucoma. The Pou6f2 knockout mouse has a thinner cornea than its wild-type littermates, while there is no apparent change in intraocular pressure. We propose that POU6F2 is expressed in novel subclasses of retinal ganglion cells (RGCs) that are sensitive to glaucomatous injury. Premise: Our four findings lead us to hypothesize that POU6F2 is in a transcriptional cascade responsible for the susceptibility and early death of a novel collection of ON-OFF directionally selective RGC subtypes. To test this hypothesis, we will focus on the role of POU6F2 in the response of RGCs in models of experimentally-induced and naturally- occurring glaucoma. The proposed experiments will uncover the POU6F2 molecular cascade that induces glaucomatous damage. We will relate our findings in the mouse to the human, through a collaboration with Dr. Janey Wiggs and the NEIGHBORHOOD consortium, interrogating the NEIGHBORHOOD meta-dataset to define molecular pathway associated with POU6F2 targets. We will determine if any of these downstream targets and their associated pathways represent factors for glaucoma risk. This basic understanding of the molecular interactions of POU6F2 will inform the rational design of strategies to improve detection of and therapy for glaucoma.