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

基本信息

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
项目类别：
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&apos 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

项目摘要

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病症是一个重要的公共卫生问题，调节眼轴生长至关重要。正常屈光发育，确保聚焦图像直接落在视网膜上。解码控制眼轴生长的分子和遗传程序。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，使得眼睛的眼轴长度与其屈光力相匹配，眼睛的内在生长增强，正视度有缺陷。被认为会导致眼轴长度与屈光力不匹配，从而导致眼轴。信号的生长依赖于视网膜到巩膜来促进细胞外基质重塑和眼部然而，信号转化为眼轴生长的机制仍然难以捉摸。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 是否对正视眼有直接作用。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，但调节其的因素 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 之间的联系我们还将在有条件的小鼠中确定 PRSS56 的视网膜表达和眼睛生长的关系（目标 1.1）。模型，无论是视网膜色素上皮 - 定位的 Serpine3 - 我们确定为候选介质 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，以指导其底物和目标的识别。在目标 3 中，我们将测试 PRSS56 在正视化和 PRSS56 依赖性调节中的作用。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。