Modulators for Retinal Ganglion Cell Injury

摘要 60岁以上美国人致盲的主要原因是青光眼。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POU6F2，它调节小鼠的中央角膜厚度，并 是人类青光眼的危险因素。Pou6f2基因敲除小鼠的角膜比野生型的要薄 下垂，而眼压没有明显变化。我们建议POU6F2表达为 对青光眼损伤敏感的视网膜神经节细胞(RGC)的新亚类。前提：我们的四个 这些发现使我们假设POU6F2处于转录级联中，与易感性和 一个新的开关方向选择性RGC亚型集合过早死亡。为了检验这一假设，我们 将重点介绍POU6F2在视网膜神经节细胞反应中的作用。 发生青光眼。拟议的实验将揭示POU6F2分子级联，它可以诱导 青光眼损害。我们将通过与Dr。 Janey Wiggs和Neighborhood财团，询问邻域元数据集以定义 与POU6F2靶点相关的分子途径。我们将确定这些下游目标中是否有任何一个 它们相关的途径代表了青光眼风险的因素。这是对分子的基本理解 POU6F2的相互作用将有助于合理设计策略，以改进对癌症的检测和治疗 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.