Role of Poldip2 in endothelial barrier function and inflammation in the lung
Poldip2 在肺内皮屏障功能和炎症中的作用
基本信息
- 批准号:10266211
- 负责人:
- 金额:$ 67.48万
- 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:2020-09-23 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsActivity CyclesAcute Lung InjuryAdherens JunctionAdult Respiratory Distress SyndromeAffectAlzheimer&aposs DiseaseAngiopoietin-2Animal ModelAnimalsArchitectureArteriesAtherosclerosisAttenuatedBacterial ToxinsBindingBlood VesselsCell Cycle RegulationCell LineCell NucleusCell membraneCellsCerebrumCessation of lifeCoronaryDNA RepairDatabasesDiabetes MellitusDiseaseEdemaEndothelial CellsEndotheliumExtracellular MatrixExtravasationFocal AdhesionsFunctional disorderGelatinase AGenesGeneticGoalsImpairmentIn VitroInflammationInflammatoryInflammatory ResponseInjuryIntegrinsIntracranial NeoplasmsIschemic StrokeKDR geneKidneyLeukocytesLipopolysaccharidesLiquid substanceLiverLungLung InflammationLymphaticMatrix MetalloproteinasesMetabolicMiddle Cerebral Artery OcclusionMitochondriaModelingMolecularMolecular ProbesMorbidity - disease rateMovementMultiple SclerosisMusNADPH OxidasePECAM1 genePathologicPathway interactionsPatientsPerinatal mortality demographicsPermeabilityPhenocopyPhenotypePhosphorylationPhysiologicalPlasma ProteinsPlayPolymerasePreventionProductionPropertyProteinsPulmonary EdemaReactive Oxygen SpeciesRegulationRoleSepsisSignal TransductionSkeletal MuscleStrokeStructure of parenchyma of lungTestingTherapeuticTight JunctionsTissuesVascular PermeabilitiesWorkblood-brain barrier disruptioncadherin 5cell typecytokinedesigndisabilityimprovedin vivoinsightlung injurymonolayermortalitynew therapeutic targetnovelnovel therapeuticsrecruitresponserhotherapeutic targetvascular bed
项目摘要
PROJECT SUMMARY
Endothelial cells line the lumen of all blood vessels and play a critical role in maintaining the barrier function
of the vasculature. Diminished barrier function and the consequent increase in vascular permeability to
plasma proteins and leukocytes has been described in pathological conditions such as acute respiratory
distress syndrome and acute lung injury. The resulting tissue edema is associated with loss of aerated
lung tissue and high mortality and morbidity. We have discovered that Polymerase delta interacting protein-
2 (Poldip2), a protein with multiple binding partners, is an important modulator of lung endothelial barrier
function. Remarkably, using a lipopolysaccharide (LPS)-induced lung injury model, we observed that
heterozygous deletion of Poldip2 nearly abolishes LPS-induced barrier dysfunction and extravasation of
leukocytes into the lung, markedly improving survival. The effect of Poldip2 depletion on permeability is
phenocopied in mice with endothelial-specific deletion of Poldip2. The phenotype of these animals is
striking, suggesting that we have identified a novel and previously unappreciated major target for diseases
related to EC barrier dysfunction. In this project, we will probe the molecular and cellular mechanisms
responsible for this impressive protection to gain insight into potential new therapies. In the first aim, we
will examine the specific role of endothelial Poldip2 in barrier function and inflammation in vivo and in vitro,
using the LPS-induced injury model. Aim 2 is designed to define the mechanisms by which endothelial
Poldip2 regulates barrier function and inflammation, focusing on the role of VE-cadherin signaling and its
interplay with angiopoietin-2, as well as the Poldip2-interacting partner Nox4. Finally, in Aim 3, we plan to
determine how Poldip2 function is regulated at the molecular and cellular levels. Together, these three
aims will allow us to gain new insight into a novel therapeutic target for prevention of protein-rich edema
and leukocyte extravasation following lung injury and will delineate the underlying molecular mechanisms.
Our work will provide insight into a fundamental mechanism regulating permeability and inflammation that
has potential broad applicability to other inflammatory diseases.
项目摘要
内皮细胞排列在所有血管的管腔中,并在维持屏障功能中起关键作用
血管系统。屏障功能减弱,血管通透性随之增加,
血浆蛋白和白细胞已经被描述为在病理状况中
窘迫综合征和急性肺损伤。由此产生的组织水肿与通气的丧失有关。
肺组织和高死亡率和发病率。我们发现聚合酶δ相互作用蛋白-
Poldip 2是一种具有多个结合伴侣的蛋白质,是肺内皮屏障的重要调节剂
功能值得注意的是,使用脂多糖(LPS)诱导的肺损伤模型,我们观察到,
Poldip 2杂合缺失几乎消除了LPS诱导的屏障功能障碍和
白细胞进入肺部,显著提高生存率。Poldip 2耗尽对渗透率的影响是
在具有Poldip 2的内皮特异性缺失的小鼠中表型复制。这些动物的表型是
令人震惊的是,这表明我们已经确定了一个新的和以前不受重视的疾病的主要目标,
与EC屏障功能障碍有关。在这个项目中,我们将探索分子和细胞机制,
负责这种令人印象深刻的保护,以深入了解潜在的新疗法。第一个目标,我们
将研究内皮Poldip 2在体内和体外屏障功能和炎症中的特定作用,
使用LPS诱导的损伤模型。目的2旨在确定内皮细胞
Poldip 2调节屏障功能和炎症,重点关注VE-钙粘蛋白信号转导及其
与血管生成素2以及Poldip 2相互作用的伴侣Nox 4相互作用。最后,在目标3中,我们计划
确定Poldip 2功能如何在分子和细胞水平上调节。在一起,这三个
aims将使我们对预防富含蛋白质的水肿的新治疗靶点有新的认识
和肺损伤后白细胞外渗,并将描绘潜在的分子机制。
我们的工作将提供对调节渗透性和炎症的基本机制的深入了解,
对其他炎症性疾病具有潜在的广泛适用性。
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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Kathy K Griendling其他文献
364 - Role of βPIX in PDGF-Induced Lamellipodia Dynamics in VSMC
- DOI:
10.1016/j.freeradbiomed.2013.10.791 - 发表时间:
2013-11-01 - 期刊:
- 影响因子:
- 作者:
Charity Duran;Holly C Williams;Bernard Lassegue;Kathy K Griendling;Alejandra San Martin - 通讯作者:
Alejandra San Martin
Kathy K Griendling的其他文献
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{{ truncateString('Kathy K Griendling', 18)}}的其他基金
Diverse Roles of Reactive Oxygen Species and Inflammation in Vascular Disease
活性氧和炎症在血管疾病中的多种作用
- 批准号:
8129768 - 财政年份:2009
- 资助金额:
$ 67.48万 - 项目类别:
Opposing roles of Nox 1 and Nox 4 in vascular physiology and pathophysiology
Nox 1 和 Nox 4 在血管生理学和病理生理学中的相反作用
- 批准号:
7788447 - 财政年份:2009
- 资助金额:
$ 67.48万 - 项目类别:
NoxR1, a regulator of Nox4-dependent cytoskeletal remodeling in vascular cells
NoxR1,血管细胞中 Nox4 依赖性细胞骨架重塑的调节因子
- 批准号:
7731077 - 财政年份:2009
- 资助金额:
$ 67.48万 - 项目类别:
Diverse Roles of Reactive Oxygen Species and Inflammation in Vascular Disease
活性氧和炎症在血管疾病中的多种作用
- 批准号:
8507552 - 财政年份:2009
- 资助金额:
$ 67.48万 - 项目类别:
Diverse Roles of Reactive Oxygen Species and Inflammation in Vascular Disease
活性氧和炎症在血管疾病中的多种作用
- 批准号:
7912906 - 财政年份:2009
- 资助金额:
$ 67.48万 - 项目类别:
Diverse Roles of Reactive Oxygen Species and Inflammation in Vascular Disease
活性氧和炎症在血管疾病中的多种作用
- 批准号:
9236298 - 财政年份:2009
- 资助金额:
$ 67.48万 - 项目类别:
Poldip2: structural and functional implications for vascular disease
Poldip2:对血管疾病的结构和功能影响
- 批准号:
9271231 - 财政年份:2009
- 资助金额:
$ 67.48万 - 项目类别:
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