Characterizing the Molecular Mechanisms of PRSS56-Dependent Ocular Growth and Refractive Error

摘要 屈光不正是全世界视力丧失的主要原因，近视和近视眼的患病率不断上升， 相关的致盲条件是一个重要的公共卫生问题。调节眼轴生长至关重要 以确保聚焦图像福尔斯直接落在视网膜上。我们的目标是 解码控制眼轴生长的分子和遗传程序。眼睛的生长是由 内在的，遗传过程在产前和产后发展（视力未调整）和产后， 视觉引导过程，正视化，被认为与内在的眼睛生长相互作用， 轴向长度匹配其光功率。增强的内在眼生长和缺陷的正视化是 被认为会导致眼轴长度和屈光力之间的不匹配，从而导致近视。眼轴 生长依赖于从视网膜到巩膜的信号，以促进细胞外基质重塑和眼内分泌。 伸长率然而，这些信号转化为眼轴生长的机制仍然难以捉摸。我们 研究表明，PRSS 56是一种分泌型丝氨酸蛋白酶，是内在机制的组成部分， 支持眼轴生长。然而，尚不清楚Prss 56是否在正视化中具有直接作用。 我们建议揭示PRSS 56依赖性屈光不正的分子和细胞过程， 发展和相关的错误，并评估PRSS 56在视觉引导的眼睛生长的作用。 尽管有证据表明PRSS 56的表达改变会影响眼轴长度，但调节其表达的因素仍然存在。 表达和介导其作用尚不清楚。Wnt介导的通路与近视相关 我们已经发现Prss 56对Wnt信号传导激动剂有应答。在目标1中，我们将阐明 通过在遗传小鼠模型中调节Wnt活性并研究其作用， 对视网膜PRSS 56表达和眼生长的影响（目的1.1）。我们还将确定，在条件鼠标 模型，无论是视网膜色素上皮定位丝氨酸3-我们确定为候选调解人 PRSS 56依赖性生长的蛋白质-帮助传递PRSS 56依赖性信号，支持眼生长（目标1.2）。 在目标2中，我们将描述PRSS 56的功能，以指导其底物的鉴定和靶向 治疗在目标3中，我们将测试PRSS 56在正视化中的作用和PRSS 56依赖性调节。 通过暂时失活PRSS 56在条件突变小鼠中的眼轴生长和使用实验 这些范例响应于视觉模糊或光学散焦而引起轴向伸长。 这些研究将为理解眼内营养不良的发生机制提供分子和遗传学框架。 生长和指导我们潜在的治疗目标，以管理近视。

Abstract Refractive errors are a major cause of vision loss worldwide, and the rising prevalence of myopia and associated blinding conditions is a significant public health concern. Regulation of ocular axial growth is critical for normal refractive development to ensure that a focused image falls directly on the retina. Our goal is to decode the molecular and genetic program that governs ocular axial growth. Ocular growth is driven by an intrinsic, genetic process during prenatal and postnatal development (vision-unadjusted) and by a postnatal, vision-guided process, emmetropization, thought to interact with intrinsic ocular growth such that the eye's axial length matches its optical power. Enhanced intrinsic ocular growth and defective emmetropization are thought to cause a mismatch between ocular axial length and optical power, leading to myopia. Ocular axial growth relies on signals from the retina to the sclera to promote extracellular matrix remodeling and ocular elongation. However, the mechanisms by which the signals translate to ocular axial growth remain elusive. Our studies suggest that PRSS56, a secreted serine protease, is a component of the intrinsic machinery that supports ocular axial growth. However, it is not known whether Prss56 has a direct role in emmetropization. We propose to uncover the molecular and cellular processes underlying PRSS56-dependent refractive development and associated errors and assess the role of PRSS56 in vision-guided ocular growth. Despite evidence that altered expression of PRSS56 affects ocular axial length, the factors that regulate its expression and mediate its effect are not known. The Wnt-mediated pathway is associated with myopia pathogenesis, and we have found that Prss56 responds to Wnt signaling agonists. In Aim 1, we will elucidate the link between Wnt and Prss56 by modulating WNT activity in genetic mouse models and studying the effect on the retinal expression of PRSS56 and ocular growth (Aim 1.1). We will also determine, in conditional mouse models, whether retinal pigment epithelium–localized Serpine3—which we identified as a candidate mediator of PRSS56-dependent growth—helps relay PRSS56-dependent signals that support ocular growth (Aim 1.2). In Aim 2, we will characterize the function of PRSS56 to guide the identification of its substrate(s) and targeted therapies. In Aim 3, we will test the role of PRSS56 in emmetropization and PRSS56-dependent regulation of ocular axial growth by temporarily inactivating PRSS56 in conditional mutant mice and using experimental paradigms that induce axial elongation in response to visual blur or optical defocus. The proposed studies will provide a molecular and genetic framework to understand the mechanisms of ocular growth and guide us to potential therapeutic targets to manage myopia.