Identification of a new role of membrane‐type 1 matrix metalloproteinases in corneal neovascularization
膜 1 型基质金属蛋白酶在角膜新生血管形成中的新作用的鉴定
基本信息
- 批准号:10585794
- 负责人:
- 金额:$ 39.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-01 至 2027-11-30
- 项目状态:未结题
- 来源:
- 关键词:Angiogenesis InhibitorsAngiogenic FactorAngiostatinsAnimal ModelAntibodiesBindingBiological AssayBiophysicsBlindnessBlood VesselsCellsCellular InfiltrationClioquinolCorneaCorneal DiseasesCorneal InjuryCorneal NeovascularizationEffectivenessEndostatinsEndothelial CellsEnzymesEquilibriumEventExtracellular MatrixExtracellular Matrix DegradationFDA approvedFGF2 geneFGFR2 geneFibroblast Growth FactorFibroblastsFolic AcidGelatinase AGelatinase BGoalsImpairmentImplantIn VitroInfectionInfiltrationInflammationInflammatoryInjuryKDR geneKnock-outKnockout MiceLeadLibrariesMMP14 geneMacrophageMatrix Metalloproteinase InhibitorMatrix MetalloproteinasesMeasuresMediatingMolecular Biology TechniquesMusNeutrophil CollagenasePharmaceutical PreparationsProteinsProteolysisRegulationReportingRoleSignal TransductionSpecificitySystemTNF-alpha converting enzymeTestingTherapeuticTherapeutic AgentsTissuesVEGFA geneValidationVascular Endothelial CellVascular Endothelial Growth Factor Receptor-1Vascular Endothelial Growth FactorsVisionWild Type Mouseanalogcell typeconditional knockoutcytokinecytotoxicityenzyme activityexperimental studyimmune cell infiltratein vivoinhibitorinjuredinnovationmembrane activitymutantnovelnovel therapeuticspigment epithelium-derived factorproMMP-2protein expressionquinolinequinoline analogreceptorscaffoldside effectsmall moleculesmall molecule inhibitor
项目摘要
Project Summary/Abstract
Corneal neovascularization (NV) can be caused by severe corneal injury or infection and is a leading cause
of blindness. Balance of pro-angiogenic factors and anti-angiogenic factors are important to maintain avascular
corneal tissue. Pro-angiogenic factors such as VEGFA and FGF2 are highly induced in inflamed corneas and
lead to activation of its receptor proteins such as VEGFR2 and FGFR2. Membrane-type 1 matrix
metalloproteinase (MMP-14) is involved in remodeling of extracellular matrix (ECM) through its proteolytic
activity. Recent studies have revealed that MMP-14 is a regulator of VEGFA/VEGFR2-mediated corneal NV via
unique and selective cleavage of VEGFR1 which is a decoy receptor for VEGFR2. FGF2-induced corneal NV is
delayed in MMP-14 knockout (KO) mice, indicating there is some correlation between FGF2 and MMP-14.
However, how MMP-14 interacts with FGF2 is still largely unknown. The goal of this application is to characterize
mechanism of MMP-14 on regulation of FGFR2 levels via ADAM-9 enzyme. We demonstrated that FGFR2 level
was low in MMP-14 KO corneal fibroblast cells. On the other hand, ADAM-9, which is substrate of MMP-14, was
higher in MMP-14 KO fibroblast than WT cells. We have also discovered that expression of MMP-8, MMP-9, and
ADAM-17, all of which are underlying FGF2/FGFR2-system, were highly induced in WT than MMP-14 KO cells
upon stimulation of FGF2. Thus, inhibition of MMP-14 can reduce FGF2/FGFR2-mediated corneal NV and
inflammation. Furthermore, our results show that FDA-approved small molecule drugs, clioquinol, chloroxine,
and folic acid, all of which contain a quinoline scaffold, inhibit MMP-14 enzyme activity. We propose three specific
aims: (1) Mechanism of two enzyme cascades, MMP-14 and ADAM-9, to regulate FGFR2 level and expression
of FGF2/FGFR2-mediated MMPs; (2) investigate the effect of MMP-14 in FGF2/FGFR2-mediated corneal
inflammation; (3) Characterize quinoline analogs as selective MMP-14 inhibitors. We will complete these aims
using innovative techniques from molecular biology and biophysics in vitro and in vivo.
项目总结/文摘
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Kyuyeon Han其他文献
Kyuyeon Han的其他文献
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{{ truncateString('Kyuyeon Han', 18)}}的其他基金
Development of MMP14-laden exosomes as a novel anti-SARS-CoV-2 therapy
开发负载 MMP14 的外泌体作为新型抗 SARS-CoV-2 疗法
- 批准号:
10591243 - 财政年份:2023
- 资助金额:
$ 39.98万 - 项目类别:
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