Inhibiting neovascularization for corneal wound healing
抑制新生血管形成促进角膜伤口愈合
基本信息
- 批准号:10557867
- 负责人:
- 金额:$ 41万
- 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:2022-03-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:AblationAcuteAnimalsAntibodiesAqueous HumorAttenuatedBindingBiochemicalBlindnessBlood VesselsBone MarrowBone Marrow TransplantationBurn injuryCASP1 geneCell DeathCell membraneCell modelCellsClinicalClustered Regularly Interspaced Short Palindromic RepeatsCorneaCorneal DiseasesCorneal InjuryCorneal NeovascularizationCytoplasmic GranulesDataDevelopmentDiseaseDisulfiramDoxycyclineEpithelial CellsEpitheliumEtiologyFibrosisFilmGeneticGrowthHealthHomeostasisHumanIn VitroInfiltrationInflammationInflammatoryInjuryInnate Immune ResponseInterleukin-1 betaKnock-outLiposomesMacrophageMediatingMembraneModelingMolecularMusMutagenesisNeutrophil InfiltrationOperative Surgical ProceduresOpticsOutcomeOutcomes ResearchPathologicPathway interactionsPatternPeptide HydrolasesPeroxidasesPersonsPhasePlayPreventionProcessProtein FamilyProteinsPublishingReactive Oxygen SpeciesRecombinantsRegulationResistanceRodent ModelRoleSafetySignal TransductionStructureTRIM FamilyTestingTissuesTopical applicationTransforming Growth Factor betaTraumaVascularizationVisionVisual impairmentWild Type Mousecorneal epithelial wound healingcorneal epitheliumcorneal regenerationcorneal scarcytokineeffective therapyexperimental studygene repairhealingimmune cell infiltrateimmune functionimprovedin vivoin vivo Modelinhibitorinjuredinjury and repairlive cell imagingmutantneovascularizationneutrophilnovelnovel therapeuticsoverexpressionoxidative damagepharmacologicpreventprotective effectrepair functionrepairedreparative processresponsetissue repairtoolwound healing
项目摘要
Project Summary
The healthy cornea is an avascular tissue which is a requirement for optical clarity and good vision. Diseases
in which the optical clarity of the cornea is lost are the third most common cause of blindness worldwide.
Various disease conditions, such as corneal injury, can result in inflammation and the pathological ingrowth
of vessels into the cornea, a process known as corneal neovascularization (CNV). Prevention of vascular
ingrowth is imperative in maintaining the health and transparency of the cornea. We have previously
demonstrated that MG53, a tissue repair gene, can promote corneal wound healing in both the epithelium
and stroma. We recently discovered that MG53 can modulate corneal inflammation and vascularization. An
approach that can functionally target multiple steps in corneal wound healing may have the potential to
significantly improve healing outcomes, leading to novel therapeutic options. MG53 is present in the human
tear film, aqueous humor, and corneal epithelial cells, supporting its potential function in corneal homeostasis
and wound healing. We show that genetic ablation of MG53 leads to pronounced corneal inflammation and
neovascularization as compared to wild type littermates. Using in vivo corneal injury models, we find that MG53
promotes corneal transparency by reducing acute inflammation and post-injury vascularization. Biochemical and
animal studies revealed that pyroptosis, a cytolytic cell death, is a novel pathway involved in post-injury CNV, as
observed in gasdermin D, a key molecule of pyroptosis, knockout corneas which were resistant to injury-induced
CNV. Further, MG53 can inhibit pyroptosis by interacting with gasdermin D, preventing its activation. In vivo
corneal wounding experiments revealed corneal pyroptosis followed neutrophil infiltration. Antibody depletion of
neutrophils completely abolished post-injury pyroptosis, suggesting infiltrating neutrophils undergoing pyroptosis
trigger secondary corneal injury and CNV. Indeed, when irradiated WT recipient mice received bone marrow
(BM) transplantation from GsdmD-/- mice, they displayed enhanced corneal healing as compared to mice that
received BM from WT mice. Experiments outlined in this project are centered on testing the hypothesis that
neutrophil pyroptosis is a key pathway that mediates corneal inflammation and CNV following injury; MG53 can
inhibit pyroptosis via preventing activation of GasdmD, thus rhMG53 can be used as an effective means to treat
corneal injury. We envision that MG53 can be applied to promote corneal healing and prevent neovascularization
after injury. The outcome of this research shall have significant translational value in developing potentially
effective therapies to treat corneal injury and neovascularization associated with corneal disease.
项目摘要
健康的角膜是一种无血管组织,它是光学清晰度和良好视力的必要条件。疾病
其中角膜的光学清晰度丧失是全世界第三大常见的致盲原因。
各种疾病状况,如角膜损伤,可导致炎症和病理性向内生长
角膜新生血管形成(CNV)是指血管进入角膜的过程。预防血管
向内生长对于维持角膜的健康和透明度是必要的。我们先前已经
表明MG 53,一种组织修复基因,可以促进角膜上皮和角膜上皮中的伤口愈合,
和基质。我们最近发现MG 53可以调节角膜炎症和血管形成。一个
在角膜伤口愈合过程中,能够在功能上靶向多个步骤的方法可能具有潜力,
显著改善愈合结果,从而产生新的治疗选择。MG 53存在于人类中。
泪膜、房水和角膜上皮细胞,支持其在角膜稳态中的潜在功能
和伤口愈合。我们发现,MG 53基因切除导致明显的角膜炎症,
新生血管形成。使用体内角膜损伤模型,我们发现MG 53
通过减少急性炎症和损伤后血管形成来促进角膜透明度。生化和
动物研究表明,细胞裂解性细胞死亡是一种新的参与损伤后CNV的途径,
在gasdermin D中观察到,gasdermin D是焦亡的关键分子,敲除角膜,
CNV.此外,MG 53可以通过与gasdermin D相互作用抑制焦亡,防止其活化。体内
角膜损伤实验显示中性粒细胞浸润后角膜焦变性。抗体耗竭
中性粒细胞完全消除了损伤后的焦亡,表明浸润的中性粒细胞发生了焦亡
引发继发性角膜损伤和CNV。事实上,当受辐射的WT受体小鼠接受骨髓移植时,
(BM)从GsdmD-/-小鼠移植,与
接受来自WT小鼠的BM。在这个项目中概述的实验集中在测试假设,
中性粒细胞焦亡是介导损伤后角膜炎症和CNV的关键途径; MG 53可以
通过抑制GasdmD的活化来抑制细胞凋亡,因此rhMG 53可以作为治疗
角膜损伤我们设想MG 53可以用于促进角膜愈合和防止新生血管形成
伤后本研究的成果将对潜在的开发具有重要的转化价值
有效治疗角膜损伤和与角膜疾病相关的新血管形成。
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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Heather Chandler其他文献
Heather Chandler的其他文献
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{{ truncateString('Heather Chandler', 18)}}的其他基金
Inhibiting neovascularization for corneal wound healing
抑制新生血管形成促进角膜伤口愈合
- 批准号:
10366187 - 财政年份:2022
- 资助金额:
$ 41万 - 项目类别:
First Aid Medicine to Treat Vesicant Induced Corneal Injury
治疗疱疹引起的角膜损伤的急救药物
- 批准号:
10487854 - 财政年份:2022
- 资助金额:
$ 41万 - 项目类别:
First Aid Medicine to Treat Vesicant Induced Corneal Injury
治疗疱疹引起的角膜损伤的急救药物
- 批准号:
10707316 - 财政年份:2022
- 资助金额:
$ 41万 - 项目类别:
Preservation of Limbal Stem Cell Function in Corneal Injury
角膜损伤后角膜缘干细胞功能的保存
- 批准号:
10457936 - 财政年份:2019
- 资助金额:
$ 41万 - 项目类别:
Preservation of Limbal Stem Cell Function in Corneal Injury
角膜损伤后角膜缘干细胞功能的保存
- 批准号:
9803337 - 财政年份:2019
- 资助金额:
$ 41万 - 项目类别:
Preservation of Limbal Stem Cell Function in Corneal Injury
角膜损伤后角膜缘干细胞功能的保存
- 批准号:
10224209 - 财政年份:2019
- 资助金额:
$ 41万 - 项目类别:
Preservation of Limbal Stem Cell Function in Corneal Injury
角膜损伤后角膜缘干细胞功能的保存
- 批准号:
10002286 - 财政年份:2019
- 资助金额:
$ 41万 - 项目类别:
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