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.

摘要 屈光不正是全球范围内导致视力丧失的主要原因，近视和 相关的致盲情况是一个重大的公共卫生问题。眼轴生长的调节至关重要 对于正常的屈光发育，确保聚焦的图像直接落在视网膜上。我们的目标是 破译控制眼轴生长的分子和遗传程序。眼睛的生长是由一种 出生前和出生后发育(视力未调整)和出生后的内在遗传过程， 视觉引导的过程，正视化，被认为与内在的眼睛生长相互作用，使眼睛的 轴向长度与其光功率相匹配。增强的内在眼生长和有缺陷的正视是 被认为导致眼轴长度和光学功率不匹配，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 伸长率。然而，这些信号转化为眼轴生长的机制仍然不清楚。我们的 研究表明，PRSS56是一种分泌型丝氨酸蛋白酶，是一种内在机制的组成部分， 支持眼轴生长。然而，目前尚不清楚Prss 56是否在正视化中起直接作用。 我们建议揭示PRSS56依赖屈光不正的分子和细胞过程 发展和相关的错误，并评估PRSS56在视觉引导眼生长中的作用。 尽管有证据表明PRSS56的表达改变会影响眼轴长度，但调节其表达的因素 其表达和调节作用尚不清楚。Wnt介导的通路与近视相关 发病机制，我们发现Prss 56对Wnt信号激动剂有反应。在目标1中，我们将阐明 Wnt与Prss 56在遗传小鼠模型中的联系及其作用研究 视网膜PRSS56的表达与眼球生长(Aim 1.1)我们还将在有条件的鼠标中确定 模型，是否视网膜色素上皮定位的Serpine3-我们确定为一个候选的介体 PRSS56-依赖生长的信号-帮助传递支持眼睛生长的PRSS56依赖的信号(目标1.2)。 在目标2中，我们将表征PRSS56的功能，以指导其底物(S)的鉴定和靶向 治疗。在目标3中，我们将测试PRSS56在正视化和PRSS56依赖的调控中的作用。 PRSS56暂时失活条件突变小鼠眼轴生长的实验研究 视觉模糊或光学散焦引起轴向伸长的范例。 建议的研究将提供一个分子和遗传学框架来理解眼部疾病的机制。 并引导我们找到潜在的治疗目标来管理近视。