Phosphatidylglycerol as a Therapy for Corneal Injury
磷脂酰甘油治疗角膜损伤
基本信息
- 批准号:10179401
- 负责人:
- 金额:$ 37.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-30 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:Adverse effectsAffectAftercareAreaBindingBiological AssayCD14 AntigenCD14 geneCell DeathCell ProliferationCellsChemical BurnsChronicConfocal MicroscopyContact LensesCorneaCorneal AbrasionCorneal InjuryDataDiabetes MellitusDiabetic mouseDiseaseDoseDry Eye SyndromesDyesEnergy-Generating ResourcesEnsureEpithelial CellsExperimental ModelsEyeGenerationsGenus HippocampusGlycolysisHeat shock proteinsHistologyImmuneImmune responseImmunologic MonitoringImpaired healingImpaired wound healingImpairmentIn VitroIndividualInfectionInfiltrationInflammationInflammation MediatorsInflammatoryInjuryInnate Immune ResponseInnate Immune SystemKnock-outKnockout MiceLipidsLiteratureMeasuresMediatingMembrane PotentialsMitochondriaMolecularMonitorMusNeutrophil InfiltrationOperative Surgical ProceduresOxidative PhosphorylationPainPathway interactionsPatientsPatternPattern recognition receptorPhosphatidylglycerolsPhospholipidsPhysiologicalProcessProductionPublishingQuality of lifeReactive Oxygen SpeciesReceptor ActivationResearchResolutionRespirationRodent ModelRoleSafetySignal TransductionSkinSkin wound healingSmall Interfering RNASterilityTLR2 geneTLR4 geneTestingTherapeuticThickTimeToll-like receptorsTopical applicationVisionWild Type MouseWound modelsalpha-Crystallinsaquaporin 3basecell injurycell motilitycorneal epithelial wound healingcorneal epitheliumcorneal regenerationdiabeticeffective therapyexperimental studyhealingimprovedin vivoin vivo Modelinnovationinstrumentknock-downmacrophagemitochondrial membranemouse modelneutralizing antibodynovelnovel therapeuticspreventresponsewoundwound healing
项目摘要
Project Summary/Abstract
Corneal wounds and abrasions occurring as a result of injury, chemical burns, surgery, contact lens wear
and dry eye syndrome are painful and can predispose individuals to infection. Although these wounds tend to
heal rapidly, in some cases, such as in diabetes, the healing may be delayed or may even fail; in other cases
individuals may continue to show persistent or chronic inflammation despite resolution of the injury or infection.
This persistent sterile inflammation can interfere with corneal clarity thereby compromising vision; therefore,
treatments to inhibit inflammation while improving corneal wound healing are needed. In exciting novel results
we have found that a naturally occurring phospholipid, dioleoylphosphatidylglycerol (DOPG), enhances corneal
epithelial wound healing in wild-type mice and in an experimental mouse model of impaired corneal wound
healing in vivo. These data suggest the possibility of using DOPG to enhance corneal wound healing
therapeutically. Information in the literature also supports a potential role for DOPG in suppressing
inflammation. Thus, we have recently demonstrated that DOPG suppresses skin inflammation by inhibiting the
activation of pattern recognition receptors, such as toll-like receptor-2 (TLR2) and toll-like receptor-4 (TLR4), in
response to damage-associated molecular patterns (DAMPs), endogenous molecules released from injured
cells to alert the innate immune system to the presence of danger so that a protective immune response can
be mounted. Indeed, a recent article examining an in vivo rodent model of sterile inflammation demonstrated
that heat shock protein B4 (HSPB4, also known as crystallin Alpha A) released from corneal keratocytes in
response to damaged corneal epithelial cells serves as a DAMP to activate TLR2 on corneal macrophages and
induce corneal inflammation. In innovative preliminary studies we have found that DOPG can inhibit
macrophage inflammatory mediator production in response to HSPB4, suggesting the likelihood that this lipid
will suppress this corneal inflammation. Based on our preliminary results, we hypothesize that DOPG will act
not only to accelerate corneal wound healing but also to suppress inflammation by inhibiting TLR2 and/or TLR4
activation. In the research proposed, we will test the idea that DOPG will: (1) dose-dependently, safely and
physiologically accelerate corneal epithelial wound healing without adverse effects, at an optimal dose to be
determined, in normal and diabetes-impaired corneal wound healing mouse models, and (2) inhibit neutrophil
infiltration and inflammation in in vivo mouse models of corneal injury through its ability to inhibit TLR2/4
activation. In a third aim we will also determine the mechanism by which DOPG exerts these effects to
stimulate corneal epithelial wound healing and inhibit TLR2/4 activation and inflammation. If our hypothesis
proves correct, it would suggest the possibility of developing DOPG as a safe and effective treatment to hasten
healing of corneal wounds and to prevent inflammation following injury, infection, ophthalmic surgery or other
disorders necessitating corneal epithelial wound healing, thereby improving the quality of life for these patients.
项目概要/摘要
由于受伤、化学烧伤、手术、佩戴隐形眼镜而发生的角膜伤口和擦伤
干眼症会带来痛苦,并且会使人容易感染。虽然这些伤口往往
愈合很快,但在某些情况下,例如糖尿病,愈合可能会延迟,甚至可能失败;在其他情况下
尽管损伤或感染已经消退,但个体可能会继续表现出持续性或慢性炎症。
这种持续的无菌性炎症会干扰角膜清晰度,从而损害视力;所以,
需要治疗来抑制炎症,同时改善角膜伤口愈合。在令人兴奋的新颖结果中
我们发现一种天然存在的磷脂,二油酰磷脂酰甘油 (DOPG),可以增强角膜
野生型小鼠和角膜伤口受损的实验小鼠模型的上皮伤口愈合
体内愈合。这些数据表明使用 DOPG 增强角膜伤口愈合的可能性
治疗上。文献中的信息也支持 DOPG 在抑制
炎。因此,我们最近证明 DOPG 通过抑制
模式识别受体的激活,例如 Toll 样受体 2 (TLR2) 和 Toll 样受体 4 (TLR4)
对损伤相关分子模式(DAMP)的反应,损伤释放的内源性分子
细胞警告先天免疫系统存在危险,以便保护性免疫反应可以
被安装。事实上,最近一篇研究无菌炎症体内啮齿动物模型的文章表明
角膜细胞释放的热休克蛋白 B4(HSPB4,也称为晶状体蛋白 Alpha A)
对受损角膜上皮细胞的反应充当 DAMP 来激活角膜巨噬细胞上的 TLR2,
诱发角膜炎症。在创新性的初步研究中,我们发现 DOPG 可以抑制
巨噬细胞响应 HSPB4 产生炎症介质,表明这种脂质可能
会抑制这种角膜炎症。根据我们的初步结果,我们假设 DOPG 会采取行动
不仅可以加速角膜伤口愈合,还可以通过抑制 TLR2 和/或 TLR4 来抑制炎症
激活。在提出的研究中,我们将测试 DOPG 的想法:(1) 剂量依赖性、安全性和
生理上加速角膜上皮伤口愈合,且无副作用,最佳剂量为
在正常和糖尿病受损的角膜伤口愈合小鼠模型中确定,并且(2)抑制中性粒细胞
通过抑制 TLR2/4 的能力,在角膜损伤的体内小鼠模型中进行浸润和炎症
激活。在第三个目标中,我们还将确定 DOPG 发挥这些作用的机制
刺激角膜上皮伤口愈合并抑制 TLR2/4 激活和炎症。如果我们的假设
证明是正确的,这表明开发 DOPG 作为一种安全有效的治疗方法的可能性,以加速
愈合角膜伤口并预防受伤、感染、眼科手术或其他原因引起的炎症
需要角膜上皮伤口愈合的疾病,从而改善这些患者的生活质量。
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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Wendy B Bollag其他文献
Association of psoriasis and stroke in end-stage renal disease patients.
终末期肾病患者牛皮癣和中风的关联。
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:3.1
- 作者:
N. Siddiquee;J. Waller;S. Baer;Azeem A. Mohammed;S. Tran;S. Padala;Lufei Young;M. Kheda;Wendy B Bollag - 通讯作者:
Wendy B Bollag
Wendy B Bollag的其他文献
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{{ truncateString('Wendy B Bollag', 18)}}的其他基金
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
- 批准号:
10373069 - 财政年份:2021
- 资助金额:
$ 37.35万 - 项目类别:
BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
- 批准号:
10618156 - 财政年份:2021
- 资助金额:
$ 37.35万 - 项目类别:
The Aquaporin-3/Phospholipase D2 Signaling Pathway in Corneal Wound Healing
角膜伤口愈合中的 Aquaporin-3/磷脂酶 D2 信号通路
- 批准号:
10664930 - 财政年份:2020
- 资助金额:
$ 37.35万 - 项目类别:
Program for Aging Research in the Summer (PARIS)
夏季老龄化研究计划(巴黎)
- 批准号:
10407548 - 财政年份:2020
- 资助金额:
$ 37.35万 - 项目类别:
Program for Aging Research in the Summer (PARIS)
夏季老龄化研究计划(巴黎)
- 批准号:
9982017 - 财政年份:2020
- 资助金额:
$ 37.35万 - 项目类别:
Program for Aging Research in the Summer (PARIS)
夏季老龄化研究计划(巴黎)
- 批准号:
10163771 - 财政年份:2020
- 资助金额:
$ 37.35万 - 项目类别:
The Aquaporin-3/Phospholipase D2 Signaling Pathway in Corneal Wound Healing
角膜伤口愈合中的 Aquaporin-3/磷脂酶 D2 信号通路
- 批准号:
10201519 - 财政年份:2020
- 资助金额:
$ 37.35万 - 项目类别:
The Aquaporin-3/Phospholipase D2 Signaling Pathway in Corneal Wound Healing
角膜伤口愈合中的 Aquaporin-3/磷脂酶 D2 信号通路
- 批准号:
10016063 - 财政年份:2020
- 资助金额:
$ 37.35万 - 项目类别:
Program for Aging Research in the Summer (PARIS)
夏季老龄化研究计划(巴黎)
- 批准号:
10624835 - 财政年份:2020
- 资助金额:
$ 37.35万 - 项目类别:
ShEEP Request for Laser Scanning Microscope (LSM) 880
ShEEP 请求激光扫描显微镜 (LSM) 880
- 批准号:
9907067 - 财政年份:2019
- 资助金额:
$ 37.35万 - 项目类别:
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