Role of insulin-like growth factor binding proteins in the pathogenesis of herpes stromal keratitis.
胰岛素样生长因子结合蛋白在疱疹基质角膜炎发病机制中的作用。
基本信息
- 批准号:10056782
- 负责人:
- 金额:$ 37.74万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAdrenal Cortex HormonesAntiviral AgentsBiological AssayBiological AvailabilityBlindnessBlocking AntibodiesBlood CirculationBlood VesselsCataractCell AgingCell surfaceChronicClinicalConfocal MicroscopyCorneaCorneal StromaCorneal edemaDevelopmentDiseaseEnzyme-Linked Immunosorbent AssayEpithelial CellsEventEye InfectionsGlaucomaGoalsHerpesvirus 1HumanHypoxiaImmunomodulatorsImpaired wound healingInfectionInflammationInflammatoryInsulin-Like Growth Factor Binding Protein 3Insulin-Like Growth Factor IInsulin-Like Growth Factor IIInsulin-Like Growth-Factor-Binding ProteinsInsulin-Like-Growth Factor I ReceptorKeratitisKnock-outKnockout MiceKnowledgeLesionLeukocytesMeasuresMembraneMolecularMusMyelogenousMyeloid CellsOralOutcomeOutcome MeasurePathogenesisPhosphorylationPhysiologic Intraocular PressurePlasmidsPredispositionProtein ArrayProteinsPublishingReceptor SignalingRecombinant Insulin-Like Growth FactorRecurrenceReportingRiskRoleSamplingSeveritiesSomatomedinsStainsSteroidsTamoxifenTestingTimeTopical applicationTyrosine Kinase InhibitorTyrosine PhosphorylationUnited StatesVascular Endothelial CellViralViral Load resultVirus ReplicationVisualangiogenesisbaseconditional knockoutcorneal epitheliumdensityexperimental studyimmunopathologyin vivomouse modelneovascularizationneutrophilnew therapeutic targetnovel therapeutic interventionpleiotropismresponsesenescence
项目摘要
Herpes stromal keratitis (HSK) is a chronic inflammatory condition that develops in response to a recurrent
corneal infection with herpes simplex virus-1 (HSV-1). HSK is the leading cause of infection-induced corneal
blindness in the United States. Clinical manifestation of HSK involves the development of opacity and
neovascularization into the avascular cornea. Newly formed leaky blood vessels in the corneal stroma obscure
the visual axis, traffic the leukocytes (mostly neutrophils) into the inflamed cornea, and cause the corneal edema.
The current mainstay of HSK treatment requires the long-term use of oral antiviral drugs and the topical
application of steroids. The prolonged use of topical steroids causes a predisposition to herpetic reactivation,
cataract development, and increased intraocular pressure (IOP), which may cause the development of
glaucoma. A better understanding of cellular and molecular events involved in the pathogenesis of HSK could
provide novel therapeutic targets to reduce the severity of HSK. The focus of this application is to understand
the mechanisms by which Insulin-like growth factor binding protein-3 (IGFBP-3) regulates the pathogenesis of
HSK. IGFBP-3 exerts its effect through insulin-like growth factor (IGF)-independent and-dependent mechanisms.
In an IGF-independent manner, IGFBP-3 is known to induce cellular senescence. The cellular senescence is
reported to inhibit viral replication. The IGF-dependent activity of IGFBP-3 involves sequestration of IGF-1 and
IGF-2 molecules and limiting their bioavailability to IGF-1R, and thereby regulates IGF-1R signaling. Our
preliminary results showed an elevated expression of IGFBP-3 in HSV-1 infected corneas of B6 mice, whereas
a significantly reduced amount of IGFBP-3 protein was detected in the circulation of infected B6 mice when
compared to uninfected B6 mice. The infected corneas of IGFBP-3 knockout (IGFBP-3 KO) mice showed an
increased viral load. Besides, increased phosphorylation of IGF-1R, the first step in IGF-1R signaling, was
determined in leukocytes infiltrating the HSK developing corneas of IGFBP-3 KO than B6 mice. A significant
increase in hemangiogenesis and opacity was measured in infected corneas of IGFBP-3 KO than B6 mice.
Together, these results led us to hypothesize that IGFBP-3 enhances viral clearance, reduces angiogenesis,
and decreases the survival and effector function of myeloid cells in HSK developing corneas. Therefore,
enhancing the IGFBP-3 protein level in HSV-1 infected cornea should alleviate the severity of HSK. Three aims
are proposed to test our hypothesis. Aim I will test the hypothesis that hypoxia enhances IGFBP-3 expression
in corneal epithelial cells, and an increased level of IGFBP-3 induces senescence in epithelial cells, and cellular
senescence promotes HSV-1 clearance from the infected cornea. Aim II will test the hypothesis that IGF-1R
signaling in myeloid and vascular endothelial cells control the severity of HSK. Aim III will test the hypothesis
that increasing IGFBP-3 protein in HSV-1 infected cornea alleviates the severity of HSK.
疱疹间质性角膜炎(HSK)是一种慢性炎症,是对复发性角膜炎的反应
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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专利数量(0)
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Susmit Suvas其他文献
Susmit Suvas的其他文献
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{{ truncateString('Susmit Suvas', 18)}}的其他基金
CXCR4: A potential therapeutic target in HSK
CXCR4:HSK 的潜在治疗靶点
- 批准号:
10752865 - 财政年份:2023
- 资助金额:
$ 37.74万 - 项目类别:
Role of insulin-like growth factor binding proteins in the pathogenesis of herpes stromal keratitis.
胰岛素样生长因子结合蛋白在疱疹基质角膜炎发病机制中的作用。
- 批准号:
10468069 - 财政年份:2020
- 资助金额:
$ 37.74万 - 项目类别:
Role of insulin-like growth factor binding proteins in the pathogenesis of herpes stromal keratitis.
胰岛素样生长因子结合蛋白在疱疹基质角膜炎发病机制中的作用。
- 批准号:
10219263 - 财政年份:2020
- 资助金额:
$ 37.74万 - 项目类别:
Role of insulin-like growth factor binding proteins in the pathogenesis of herpes stromal keratitis.
胰岛素样生长因子结合蛋白在疱疹基质角膜炎发病机制中的作用。
- 批准号:
10673185 - 财政年份:2020
- 资助金额:
$ 37.74万 - 项目类别:
Interplay between hypoxia and oxidative phosphorylation in herpes stromal keratitis
疱疹性基质角膜炎中缺氧与氧化磷酸化之间的相互作用
- 批准号:
10357859 - 财政年份:2019
- 资助金额:
$ 37.74万 - 项目类别:
Interplay between hypoxia and oxidative phosphorylation in herpes stromal keratitis
疱疹性基质角膜炎中缺氧与氧化磷酸化之间的相互作用
- 批准号:
10586030 - 财政年份:2019
- 资助金额:
$ 37.74万 - 项目类别:
Corneal neuropeptides and herpetic stromal keratitis
角膜神经肽与疱疹性基质角膜炎
- 批准号:
8616376 - 财政年份:2013
- 资助金额:
$ 37.74万 - 项目类别:
Corneal neuropeptides and herpetic stromal keratitis
角膜神经肽与疱疹性基质角膜炎
- 批准号:
8504248 - 财政年份:2013
- 资助金额:
$ 37.74万 - 项目类别:
Corneal neuropeptides and herpetic stromal keratitis
角膜神经肽与疱疹性基质角膜炎
- 批准号:
9248405 - 财政年份:2013
- 资助金额:
$ 37.74万 - 项目类别:
Corneal neuropeptides and herpetic stromal keratitis
角膜神经肽与疱疹性基质角膜炎
- 批准号:
8912631 - 财政年份:2013
- 资助金额:
$ 37.74万 - 项目类别:














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