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:
- 金额:$ 40.38万
- 依托单位:
- 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:
- 关键词:AffectAgonistAnimal ModelAttentionBiochemicalBlindnessCallithrixCell Culture TechniquesCell physiologyClinicalCuesDefectDeletion MutationDependovirusDevelopmentDiseaseEnsureExtracellular MatrixEyeGene TargetingGeneticGenetic ProcessesGenetic studyGlaucomaGoalsGrowthGrowth FactorHumanHyperopiaImageIndividualInterventionInvestigationLengthLinkMacular degenerationMediatingMediator of activation proteinMessenger RNAMicrophthalmosModernizationMolecularMolecular GeneticsMuller&aposs cellMusMutant Strains MiceMutationMyopiaOpticsPathogenesisPathway interactionsPrevalenceProcessProteomicsPublic HealthRefractive ErrorsRegulationRetinaRetinal DetachmentRiskRoleScleraSeriesSerine ProteaseSerine Proteinase InhibitorsSignal TransductionStructure of retinal pigment epitheliumTestingTimeTransgenic OrganismsTranslatingVariantVisionVisualWNT Signaling Pathwaybeta catenincell typeconditional mutantdeprivationemmetropizationexperimental studyfallsgenetic approachinsightlensmouse modelnew therapeutic targetoverexpressionpostnatalpostnatal developmentprenatalpreventprogramsresponsetargeted treatmenttherapeutic targettrypsin-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.
摘要
项目成果
期刊论文数量(0)
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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
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:
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