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：
10367868
负责人：
Kayarat Saidas Nair
金额：
$ 40.38万
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/10367868
关键词：
Affect Agonist Animal Model Attention Biochemical Blindness Callithrix Cell Culture Techniques Cell physiology Clinical Cues Defect Deletion Mutation Dependovirus Development Disease Ensure Extracellular Matrix Eye Gene Targeting Genetic Genetic Processes Genetic study Glaucoma Goals Growth Growth Factor Human Hyperopia Image Individual Intervention Investigation Length Link Macular degeneration Mediating Mediator of activation protein Messenger RNA Microphthalmos Modernization Molecular Molecular Genetics 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 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.

抽象的屈光错误是全球视力丧失的主要原因，近视和近视的患病率上升相关的盲目条件是一个重大的公共卫生问题。监管眼轴向生长至关重要对于正常的折射率，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部轴向生长的分子和遗传程序。眼增长是由产前和产后发育期间的固有，遗传过程（无视力未经调查），并通过产后，视觉引导的过程，弹性化，被认为与内在的眼部生长相互作用，以使眼睛的生长轴向长度与其光学功率匹配。增强的内在眼生长和有缺陷的弹性化是被认为会导致眼部轴向长度和光学功率之间的不匹配，从而导致近视。眼轴向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伸长。但是，信号转化为眼部轴向生长的机制仍然难以捉摸。我们的研究表明，PRSS56是一种分泌的丝氨酸蛋白酶，是内在机械的一个组成部分，支持眼部轴向生长。但是，尚不知道Press56在弹性化中是否具有直接作用。我们建议揭示PRSS56依赖性折射的分子和细胞过程开发和相关的错误和评估PRSS56在视觉引导的眼部生长中的作用。尽管有证据表明PRSS56的表达改变会影响眼部轴向长度，但调节其的因素表达并介导其效果尚不清楚。 WNT介导的途径与近视有关发病机理，我们发现Press56对Wnt信号激动剂做出反应。在AIM 1中，我们将阐明 Wnt和Press56之间通过调节遗传小鼠模型中的Wnt活性并研究效果的连接关于PRSS56和眼部生长的视网膜表达（AIM 1.1）。我们还将在条件鼠标中确定模型，视网膜色素上皮 - 局部serpine3-我们确定为候选介体 PRSS56依赖性生长 - 支持眼增长的助 - 继电器PRSS56依赖性信号（AIM 1.2）。在AIM 2中，我们将表征PRSS56的功能，以指导其底物的识别并针对目标疗法。在AIM 3中，我们将测试PRSS56在弹性化和PRSS56依赖性调节中的作用通过在条件突变小鼠中暂时灭活PRSS56的眼部轴向生长，并使用实验响应视觉模糊或光学散焦而影响轴向伸长的范例。拟议的研究将提供一个分子和遗传框架，以了解眼的机制成长并指导我们实现管理近视的潜在治疗靶标。