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
基本信息
- 批准号:10201519
- 负责人:
- 金额:--
- 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:2020-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectBlindnessCell Cycle ProgressionCell ProliferationCell physiologyCellsCellular biologyCorneaCorneal InjuryDataEnzymesEpidermal Growth FactorEpidermal Growth Factor ReceptorEpithelial Cell ProliferationEpithelial CellsEtiologyEventExhibitsFamilyGenetic EngineeringGlycerolHumanImpaired wound healingImpairmentIn SituIn VitroIndividualInfectionInjuryKnockout MiceLaboratoriesLeadLeukemic CellLigandsLipidsLiteratureModelingMonitorMusOperative Surgical ProceduresPKC-betaIIPainPatientsPharmacologyPhenotypePhosphatidylglycerolsPhospholipaseProcessProductionProtein KinaseProtein Kinase CRNA InterferenceReportingResearchRoleSecond Messenger SystemsSignal PathwaySignal TransductionSignaling MoleculeSkinSkin wound healingSystemTestingTraumaVisionWorkaquaporin 3basecell motilitycell typecorneal epithelial wound healingcorneal epitheliumhealingin vivoinhibitor/antagonistkeratinocyteknockout animallimbalmigrationmouse modelnoveloverexpressionphospholipase D2protein Eprotein activationprotein kinase C betaresponsetherapy developmentwound closurewound healing
项目摘要
Project Summary/Abstract
Previous data from our laboratory indicate that the lipid-metabolizing enzyme phospholipase D2 (PLD2)
and the glycerol transporter aquaporin-3 (AQP3) physically and functionally interact in epidermal keratinocytes.
AQP3 transports glycerol into the cell, making it available to the associated PLD2, which converts it to
phosphatidylglycerol (PG). Our results further demonstrate that PG acts as a lipid second messenger to
promote epidermal wound healing. Verkman and colleagues have generated an AQP3 knockout mouse model,
which shows a profound epidermal phenotype including delayed skin wound healing. Interestingly, and of
direct significance to this application, these AQP3 knockout mice also exhibit impaired corneal wound healing.
Inspection of the literature suggests that epidermal keratinocytes and corneal epithelial cells show a number of
similarities and may be regulated by common mechanisms. In exciting preliminary data we have found that
PLD2 and AQP3 also associate in corneal epithelial cells and that the product of this interaction, PG, enhances
scratch wound closure of corneal epithelial cells in culture as well as corneal wound healing in wild-type and
AQP3 knockout mice in vivo. These findings lead us to hypothesize that the PLD2/AQP3/PG signaling module
is important in the cornea. Because these effects of PG are reminiscent of the actions of epidermal growth
factor receptor (EGFR) ligands on corneal epithelium, we specifically hypothesize that PLD2 and AQP3
associate in corneal epithelial cells to produce PG in response to EGFR ligands and that this PG acts as a
signaling molecule to accelerate wound healing in the cornea by increasing epithelial cell migration and/or
proliferation. In the research proposed, we will test this hypothesis and define the role of the PLD2/AQP3
signaling module in corneal cell biology and wound healing. Data in the literature and our own initial results in
epidermal keratinocytes indicate that PG can activate protein kinase CβII (PKCβII). Based on these data, as
well as reports that PKCβ inhibition or silencing can inhibit corneal proliferation and proliferative signaling, we
further hypothesize that the mechanism by which the PLD2/AQP3 model functions is through PG-activated
PKCβII activation. We will test this idea using knockout animals, as well as overexpression, RNA interference,
and pharmacological inhibition approaches to increase and decrease the levels of PLD2, AQP3 and PKCβII;
we will then monitor corneal epithelial cell migration and proliferation, PG levels, PKCβII autophosphorylation
(activation) and corneal wound healing in vivo. If our hypothesis proves correct, the research will lead to a
better understanding of the corneal epithelial wound healing process and may lead to the identification of novel
targets for the development of treatments to promote corneal would healing in patients after trauma, infection
or ophthalmic surgery.
项目摘要/摘要
本实验室以往的数据表明,脂代谢酶磷脂酶D2(PLD2)
而甘油转运体水通道蛋白-3(AQP3)与表皮角质形成细胞在物理和功能上相互作用。
AQP3将甘油输送到细胞内,使其可供关联的PLD2使用,后者将甘油转化为
磷脂酰甘油(PG)。我们的结果进一步证明PG是脂质的第二信使
促进表皮创面愈合。Verkman和他的同事已经产生了一种AQP3基因敲除小鼠模型,
这显示了一种深刻的表皮表型,包括皮肤伤口愈合延迟。有趣的是,
对于这一应用的直接意义是,这些AQP3基因敲除的小鼠也表现出角膜伤口愈合受损。
对文献的检查表明,表皮角质形成细胞和角膜上皮细胞显示出许多
它们有相似之处,并可能受到共同机制的制约。在令人兴奋的初步数据中,我们发现
PLD2和AQP3在角膜上皮细胞中也有关联,这种相互作用的产物PG增强
培养的角膜上皮细胞的划痕伤口闭合以及角膜伤口的愈合
体内AQP3基因敲除小鼠。这些发现使我们假设PLD2/AQP3/PG信号模块
在角膜中很重要。因为PG的这些作用让人联想到表皮生长的作用
与角膜上皮细胞上的因子受体(EGFR)配体一样,我们特别假设PLD2和AQP3
在角膜上皮细胞中结合以产生PG以响应EGFR配体,并且这种PG作为一种
通过促进角膜上皮细胞迁移和/或促进伤口愈合的信号分子
扩散。在提出的研究中,我们将检验这一假设,并定义PLD2/AQP3的作用
角膜细胞生物学和伤口愈合中的信号模块。文献中的数据和我们自己在
表皮角质形成细胞提示PG可激活蛋白激酶CβII(PKCβII)。根据这些数据,如
以及pkcβ抑制或沉默可以抑制角膜增殖和增殖信号的报道,我们
进一步假设PLD2/AQP3模型的作用机制是通过PG激活的
PKCβII激活。我们将使用基因敲除动物以及过度表达、RNA干扰、
提高和降低PLD2、AQP3和PKCβII水平的药理抑制途径;
然后我们将监测角膜上皮细胞的迁移和增殖,PG水平,PKCβII自动磷酸化
(激活)和体内角膜伤口愈合。如果我们的假设被证明是正确的,这项研究将导致
更好地了解角膜上皮损伤的愈合过程,并可能导致新的识别
发展促进角膜治疗的目标是促进创伤、感染后患者的愈合
或者眼科手术。
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
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:
-- - 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:
-- - 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:
-- - 项目类别:
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