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

表征 PRSS56 依赖性眼生长和屈光不正的分子机制

• 批准号: 10705558
• 负责人: Kayarat Saidas Nair
• 金额: $ 39.94万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705558
• 关键词: Acceleration; Affect; Agonist; Animal Model; Attention; Biochemical; Blindness; Callithrix; Cell Culture Techniques; Cell physiology; Clinical; Cues; Defect; Deletion Mutation; Dependovirus; Development; Disease; Extracellular Matrix; Eye; Gene Targeting; Genetic; Genetic Processes; Genetic study; Glaucoma; Goals; Growth; Human; Hyperopia; Image; Individual; Intervention; Intrinsic drive; Investigation; Length; Link; Macular degeneration; Mediating; Mediator; Messenger RNA; Microphthalmos; Modernization; Molecular; Muller' s cell; Mus; Mutant Strains Mice; Mutation; Myopia; Optics; Pathogenesis; Pathway interactions; Prevalence; Process; Proteomics; Public Health; Refractive Errors; Regulation; Retina; Retinal Detachment; Risk; Role; Sclera; Series; Serine Protease; Serine Proteinase Inhibitors; Signal Transduction; Structure of retinal pigment epithelium; Testing; Time; Transgenic Organisms; Translating; Variant; Vision; Visual; WNT Signaling Pathway; beta catenin; cell type; conditional mutant; deprivation; emmetropization; experimental study; falls; genetic approach; insight; lens; lens induction; mouse model; new therapeutic target; overexpression; postnatal; postnatal development; prenatal; prevent; programs; response; targeted treatment; therapeutic target; trypsin-like serine protease

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.

抽象的 屈光不正是全世界视力丧失的主要原因，近视和近视患病率不断上升 相关的致盲情况是一个重大的公共卫生问题。调节眼轴生长至关重要 用于正常屈光发育，以确保聚焦图像直接落在视网膜上。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 产前和产后发育（视力未调整）和产后的内在遗传过程， 视觉引导过程，正视化，被认为与内在的眼睛生长相互作用，使得眼睛的 轴向长度与其光功率相匹配。增强的内在眼睛生长和有缺陷的正视化 据认为会导致眼轴长度和屈光度不匹配，从而导致近视。眼轴 生长依赖于从视网膜到巩膜的信号来促进细胞外基质重塑和眼睛 伸长。然而，信号转化为眼轴生长的机制仍然难以捉摸。我们的 研究表明，PRSS56（一种分泌型丝氨酸蛋白酶）是内在机制的一个组成部分， 支持眼轴生长。然而，尚不清楚Prss56是否在正视化中具有直接作用。 我们建议揭示 PRSS56 依赖性屈光背后的分子和细胞过程 发育和相关错误并评估 PRSS56 在视觉引导眼部生长中的作用。 尽管有证据表明 PRSS56 表达的改变会影响眼轴长度，但调节其长度的因素 其表达和介导其作用尚不清楚。 Wnt介导的通路与近视有关 发病机制，我们发现Prss56对Wnt信号激动剂有反应。在目标 1 中，我们将阐明 通过在遗传小鼠模型中调节 WNT 活性并研究其效果，揭示 Wnt 和 Prss56 之间的联系 PRSS56 的视网膜表达和眼睛生长的关系（目标 1.1）。我们还将确定，在有条件的鼠标 模型，无论是视网膜色素上皮细胞——定位的 Serpine3——我们将其确定为候选介质 PRSS56 依赖性生长——帮助传递支持眼睛生长的 PRSS56 依赖性信号（目标 1.2）。 在目标 2 中，我们将描述 PRSS56 的功能，以指导识别其底物和目标 疗法。在目标 3 中，我们将测试 PRSS56 在正视化中的作用以及 PRSS56 依赖性调节 通过暂时灭活条件突变小鼠中的 PRSS56 并使用实验 响应视觉模糊或光学散焦而引起轴向伸长的范例。 拟议的研究将为理解眼部疾病的机制提供分子和遗传框架。 增长并指导我们找到控制近视的潜在治疗目标。