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

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.
摘要

项目成果

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Kayarat Saidas Nair其他文献

Kayarat Saidas Nair的其他文献

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{{ truncateString('Kayarat Saidas Nair', 18)}}的其他基金

Diversity Supplement_Torres
多样性补充_托雷斯
  • 批准号:
    10674359
  • 财政年份:
    2022
  • 资助金额:
    $ 40.38万
  • 项目类别:
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
  • 财政年份:
    2022
  • 资助金额:
    $ 40.38万
  • 项目类别:
Determining Molecular Mechanisms of Human Glaucoma Genes
确定人类青光眼基因的分子机制
  • 批准号:
    10444972
  • 财政年份:
    2022
  • 资助金额:
    $ 40.38万
  • 项目类别:
Determining Molecular Mechanisms of Human Glaucoma Genes
确定人类青光眼基因的分子机制
  • 批准号:
    10612930
  • 财政年份:
    2022
  • 资助金额:
    $ 40.38万
  • 项目类别:
Determining Molecular and Cellular Mechanisms of Glaucoma
确定青光眼的分子和细胞机制
  • 批准号:
    9211347
  • 财政年份:
    2014
  • 资助金额:
    $ 40.38万
  • 项目类别:
Determining Molecular and Cellular Mechanisms of Glaucoma
确定青光眼的分子和细胞机制
  • 批准号:
    8788029
  • 财政年份:
    2014
  • 资助金额:
    $ 40.38万
  • 项目类别:
Determining Molecular and Cellular Mechanisms of Glaucoma
确定青光眼的分子和细胞机制
  • 批准号:
    8784082
  • 财政年份:
    2014
  • 资助金额:
    $ 40.38万
  • 项目类别:
Determining Molecular and Cellular Mechanisms of Glaucoma
确定青光眼的分子和细胞机制
  • 批准号:
    9003054
  • 财政年份:
    2014
  • 资助金额:
    $ 40.38万
  • 项目类别:
Determining Molecular and Cellular Mechanisms of Glaucoma
确定青光眼的分子和细胞机制
  • 批准号:
    8418312
  • 财政年份:
    2013
  • 资助金额:
    $ 40.38万
  • 项目类别:
Morphology Core
形态核心
  • 批准号:
    10665568
  • 财政年份:
    1997
  • 资助金额:
    $ 40.38万
  • 项目类别:

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