Molecular mechanisms of corneal recurrent erosion formation
角膜反复糜烂形成的分子机制
基本信息
- 批准号:8388623
- 负责人:
- 金额:$ 58.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1992
- 资助国家:美国
- 起止时间:1992-07-01 至 2016-06-30
- 项目状态:已结题
- 来源:
- 关键词:AgingAmericanApoptosisApoptoticBasement membraneBiological Response ModifiersCell-Matrix JunctionCellsChronicCleaved cellCorneaCorneal InjuryCorneal StromaCorneal dystrophyDataDebridementDevelopmentEpithelial CellsEventEyeFibroblastsFrequenciesFundingGenotypeGoalsHealedHeparan Sulfate ProteoglycanHumanImmuneIn VitroInferiorInflammationInflammatoryInheritedInjuryIntegrinsKnockout MiceLeadLeftLeukocytesMMP9 geneMatrix MetalloproteinasesMediatingModelingMolecularMouse StrainsMusNerveNerve FibersNoseOperative Surgical ProceduresPTPRC genePainPathologyPatientsPlayProductivityQuality of lifeRecruitment ActivityRecurrenceResolutionRoleSecondary toSignal TransductionStromal CellsStructure of nail of fingerStudy modelsSurfaceT-LymphocyteTestingTraumaUp-RegulationVisionWorkWound Healingafferent nervebasecell injurycell motilitycell typecorneal epitheliumcytokinehealingimprovedin vivoinjuredinsightkeratinocytemicroorganismnerve supplyneutralizing antibodyocular surfacepreventreinnervationsyndecan
项目摘要
DESCRIPTION (provided by applicant): Corneal surface injuries are painful and expose the eye to infectious microorganisms that can destroy vision. During our previous funding period, we developed and characterized a model for the study of recurrent corneal erosions in mice that uses a dulled blade to create debridement wounds. The erosions we study in the mouse cornea after dulled blade wounds serve as a model to understand the causes of the recurrent corneal erosions that occur in patients after superficial wounds such as fingernail injuries as well as secondary to inherited corneal dystrophies. We have shown that erosions form primarily in the inferior nasal quadrant and that MMP9 expression is elevated in the corneal epithelium before and after erosion formation. Furthermore, MMP9 associates with and cleaves hemidesmosomal a6b4 integrin. Despite slower wound healing and prolonged inflammation, mice lacking the heparan sulfate proteoglycan syndecan-1 (sdc1) have 50% fewer corneal erosions in vivo and cells isolated from sdc1 null mice have differences in integrin-mediated cell migration and TGFb1 signaling in vitro. The long-term goal of this project is to identify those factors that prevent the corneal epithelium from reforming an intact barrier after trauma to the ocular surface. Based on our past work and preliminary data, we hypothesize that recurrent erosions form after dulled blade wounds due to immune mediators released by damaged sensory nerves, apoptotic corneal stromal cells, and immune cells. This leads to poor reinnervation of sub-basal nerves and reduced activation of corneal stromal cells that combine to prevent formation of stable cell:matrix adhesions by corneal epithelial cells. To test this hypothesis we propose the following Aims: 1. Eliminate erosion formation after dulled blade wounds by altering immune cell recruitment. 2. Induce resolution of erosions after they form by manipulating the proliferation and activation of corneal stromal cells and reinnervation of sub-basal nerves. 3. Determine the role of TGFb1 signaling in the formation of erosions by treating mice with TGFb1 and TGFb1 neutralizing antibodies in vivo after dulled blade and rotating burr wounds and in vitro using corneal stromal cells and mouse keratinocytes. By understanding the molecular and cellular causes of chronic corneal inflammation and erosions, we will be better able to facilitate their resolution in mice and in people.
PUBLIC HEALTH RELEVANCE: Corneal surface injuries are the major ophthalmic complaint. Recurrent erosions can develop after ocular trauma and chronic inflammation of the ocular surface interferes with the quality of life and productivity of millions of Americans; reduced innervation of the cornea by sensory nerves occurs after cornea surgery and with aging and plays a role in development of erosions. By characterizing the cytokines and immune cell types that prevent resolution of corneal wound healing as well as those that promote resolution, we will gain the insight needed to improve the quality of life for those suffering from ocular surface
inflammatory conditions secondary to trauma.
描述(由申请人提供):角膜表面损伤疼痛,并使眼睛暴露于可破坏视力的感染性微生物。在我们之前的资助期间,我们开发并表征了一种用于研究小鼠复发性角膜糜烂的模型,该模型使用钝刀片来创建清创伤口。我们研究的小鼠角膜钝刀片伤口后的糜烂作为一个模型,以了解复发性角膜糜烂的原因,发生在患者的浅表伤口,如指甲损伤,以及继发于遗传性角膜营养不良。我们已经发现糜烂主要形成于鼻下象限,并且在糜烂形成之前和之后,MMP 9在角膜上皮中的表达升高。此外,MMP 9与半桥粒α 6 β 4整联蛋白结合并切割半桥粒α 6 β 4整联蛋白。尽管伤口愈合较慢和炎症延长,缺乏硫酸乙酰肝素蛋白聚糖syndecan-1(sdc 1)的小鼠体内角膜糜烂减少50%,从sdc 1缺失小鼠分离的细胞在体外整合素介导的细胞迁移和TGF β 1信号传导方面存在差异。本项目的长期目标是确定那些阻止角膜上皮在眼表创伤后重新形成完整屏障的因素。根据我们过去的工作和初步数据,我们假设,钝刀片伤口后,由于受损的感觉神经,凋亡的角膜基质细胞和免疫细胞释放的免疫介质,复发性糜烂的形式。这导致基底下神经的再神经支配不良和角膜基质细胞的活化减少,所述角膜基质细胞结合联合收割机以防止角膜上皮细胞形成稳定的细胞:基质粘附。为了验证这一假设,我们提出以下目标:1。通过改变免疫细胞的募集来消除钝刃伤口后的侵蚀形成。2.通过操纵角膜基质细胞的增殖和激活以及基底下神经的再支配,诱导糜烂形成后的消退。3.通过在钝刀片和旋转磨头伤口后在体内用TGF β 1和TGF β 1中和抗体处理小鼠,以及在体外使用角膜基质细胞和小鼠角质形成细胞,确定TGF β 1信号传导在糜烂形成中的作用。通过了解慢性角膜炎症和糜烂的分子和细胞原因,我们将能够更好地促进它们在小鼠和人类中的解决。
公共卫生相关性:角膜表面损伤是主要的眼科主诉。复发性糜烂可在眼外伤后发展,眼表的慢性炎症干扰了数百万美国人的生活质量和生产力;角膜手术后感觉神经对角膜的神经支配减少,随着年龄的增长,在糜烂的发展中起作用。通过表征阻止角膜伤口愈合消退以及促进消退的细胞因子和免疫细胞类型,我们将获得改善眼表疾病患者生活质量所需的洞察力。
继发于创伤的炎症。
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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Mary Ann Stepp其他文献
Mary Ann Stepp的其他文献
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{{ truncateString('Mary Ann Stepp', 18)}}的其他基金
MOLECULAR ASPECTS OF CORNEAL EPITHELIAL MIGRATION
角膜上皮迁移的分子方面
- 批准号:
2162301 - 财政年份:1992
- 资助金额:
$ 58.68万 - 项目类别:
MOLECULAR ASPECTS OF CORNEAL EPITHELIAL MIGRATION
角膜上皮迁移的分子方面
- 批准号:
2162302 - 财政年份:1992
- 资助金额:
$ 58.68万 - 项目类别:
MOLECULAR ASPECTS OF CORNEAL EPITHELIAL MIGRATION
角膜上皮迁移的分子方面
- 批准号:
3265840 - 财政年份:1992
- 资助金额:
$ 58.68万 - 项目类别:
Molecular Aspects of Corneal Epithelial Migration
角膜上皮迁移的分子方面
- 批准号:
7880422 - 财政年份:1992
- 资助金额:
$ 58.68万 - 项目类别:
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