The Role of Adaptor Protein Disabled-2 in Maintaining Endothelial Cell Function in Atherosclerosis
接头蛋白Disabled-2在维持动脉粥样硬化内皮细胞功能中的作用
基本信息
- 批准号:10532247
- 负责人:
- 金额:$ 76.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-12-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAdaptor Signaling ProteinAdvanced DevelopmentAnimal ModelAortaApoE knockout mouseApolipoprotein EArterial Fatty StreakArtificial nanoparticlesAtherosclerosisBindingBiological AvailabilityBirthBlood VesselsBreedingCardiovascular DiseasesCause of DeathCell physiologyCellsClathrinComplementComplexCuriositiesDataDevelopmentDisabled Homolog 2 ProteinDisabled PersonsEndocytosisEndosomesEndothelial CellsEndotheliumEnsureEventExhibitsFoundationsFunctional disorderGene ActivationGene ExpressionGenesGoalsGrowthHealthHeart DiseasesHumanImmuneImpairmentIn VitroInflammationInflammatoryInterleukin-6InvestigationKnockout MiceLesionLow-Density LipoproteinsMAP4MediatingMedicalMessenger RNAMicroscopyMissionModelingMolecularMorbidity - disease rateMusMyocardial InfarctionNOS3 geneNanotechnologyPIK3CG genePathway interactionsPatientsPhosphotransferasesPilot ProjectsPlayProductionProteinsQuantitative Reverse Transcriptase PCRReagentReportingResearchResolutionRiskRoleRuptureSignal PathwaySignal TransductionStrokeTNF geneTechnologyTestingTherapeuticTumor Suppressor ProteinsUbiquitinUbiquitinationUnited StatesUnited States National Institutes of HealthVasodilationWorkatherogenesisatheroprotectiveclinically relevantclinically significantcombateffective therapyendothelial dysfunctionepsininhibitorinnovationmRNA deliverymortalitynanoparticlenew therapeutic targetnovelnovel therapeuticsoxidized low density lipoproteinparticlepreventrecruitresponserestraintsharpinshear stressstemtargeted deliverytraffickingtranscriptome sequencingwestern diet
项目摘要
PROJECT SUMMARY/ABSTRACT
Cardiovascular diseases are often associated with impaired responses from the endothelium, which results
from endothelial cell dysfunction. Endothelial cell dysfunction causes endothelial activation and sub-endothelial
retention of modified low-density lipoprotein (LDL) particles, leading to the recruitment of immune and
inflammatory cells to the intima, which initiate atheromatous plaque build-up. Of major importance, transitioning
from a stable to vulnerable atheroma fuels myocardial infarction and stroke, posing enormous health
challenges with the highest morbidity and mortality in the United States. New research is urgently needed to
uncover critical pathophysiological mechanisms and identify molecules that limit endothelial dysfunction. This
has led us to determine a novel and indispensable role for an endocytic adaptor protein called Disabled
homolog 2 (Dab2), which participates in clathrin-mediated endocytosis in addition to moonlighting as a tumor
suppressor. Curiously, little to no prior work has been done to identify its role in endothelial cells. Our pilot
assessment has revealed that Dab2 levels are strikingly decreased in the atherosclerotic endothelium of
mouse and human fatty streaks—suggesting a protective role in atherogenesis. As the atheroprotective effects
of Dab2 are poorly understood in the context of endothelial cells, we created endothelial-specific inducible
Dab2 knockout mice (EC-iDab2KO) and bred them to an ApoE-null background (EC-Dab2iKO/ApoE-/-).
Western diet-fed EC-iDab2KO/ApoE-/- mice exhibit heightened arterial inflammation and more severe plaque
formation; yet, the molecular mechanisms and signaling pathways that direct Dab2 to combat arterial
inflammation are completely unknown. Our initial investigation indicates that Dab2 expression is upregulated in
response to atheroprotective flow, and Dab2 deficiency in human aortic endothelial cells suppresses
endothelial nitric oxide synthase (eNOS) activation. To ensure the clinical relevance of our work, we are
employing an innovative nanotechnology to deliver Dab2 mRNA to the atherogenic endothelium using an
engineered nanoparticle to restore Dab2 function. This technology increases Dab2 expression in the atheroma,
which restrains plaque progression in ApoE-/- mice. The goal of this proposal is to define the signaling
mechanisms underpinning the essential role of Dab2 in protecting the atherogenic endothelium. To this end,
we seek to determine molecular mechanisms by which Dab2 curbs arterial inflammation and activates eNOS in
endothelial cells. Our possession of innovative targeting reagents and novel animal models will greatly facilitate
our paradigm-shifting endeavor. If fruitful, the exciting work proposed in our application will provide a
foundation for the development of new treatments to benefit patients at-risk for heart attacks and strokes.
项目总结/摘要
心血管疾病通常与内皮细胞的反应受损有关,这导致
内皮细胞功能障碍内皮细胞功能障碍导致内皮细胞活化和亚内皮细胞活化。
修饰的低密度脂蛋白(LDL)颗粒的保留,导致免疫和
炎性细胞向内膜迁移,引发动脉粥样硬化斑块的形成。最重要的是,
从稳定的动脉粥样硬化到脆弱的动脉粥样硬化会引发心肌梗死和中风,
美国发病率和死亡率最高的挑战。迫切需要新的研究,
揭示关键的病理生理机制,并确定限制内皮功能障碍的分子。这
使我们确定了一种称为Disabled的内吞衔接蛋白的新的不可或缺的作用
同源物2(Dab 2),除了作为肿瘤兼职外,还参与网格蛋白介导的内吞作用
抑制器。奇怪的是,很少或没有先前的工作已经确定其在内皮细胞中的作用。我们的飞行员
评估显示Dab 2水平在动脉粥样硬化内皮细胞中显著降低,
小鼠和人的脂肪条纹-提示在动脉粥样硬化形成中的保护作用。由于抗动脉粥样硬化作用
Dab 2在内皮细胞的背景下知之甚少,我们创建了内皮特异性诱导的
Dab 2敲除小鼠(EC-iDab 2KO),并将其与ApoE-无效背景(EC-Dab 2 iKO/ApoE-/-)交配。
西方饮食喂养的EC-iDab 2KO/ApoE-/-小鼠表现出升高的动脉炎症和更严重的斑块
形成;然而,指导Dab 2对抗动脉粥样硬化的分子机制和信号通路,
炎症完全未知。我们的初步研究表明,Dab 2表达上调,
对动脉粥样硬化保护性血流的反应,以及人主动脉内皮细胞中Dab 2缺陷抑制
内皮型一氧化氮合酶(eNOS)激活。为了确保我们工作的临床相关性,我们
采用创新的纳米技术,使用一种药物将Dab 2 mRNA递送到致动脉粥样硬化的内皮细胞,
工程纳米颗粒,以恢复Dab 2功能。该技术增加了动脉粥样硬化中Dab 2的表达,
其抑制ApoE-/-小鼠中的斑块进展。本提案的目标是定义信令
支持Dab 2在保护致动脉粥样硬化内皮中的重要作用的机制。为此目的,
我们试图确定Dab 2抑制动脉炎症和激活eNOS的分子机制,
内皮细胞我们拥有创新的靶向试剂和新型动物模型,
我们改变范式的奋进如果富有成效,我们申请中提出的令人兴奋的工作将提供一个
该基金会致力于开发新的治疗方法,以造福有心脏病发作和中风风险的患者。
项目成果
期刊论文数量(0)
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Hong Chen其他文献
Hong Chen的其他文献
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{{ truncateString('Hong Chen', 18)}}的其他基金
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- 批准号:
10576675 - 财政年份:2022
- 资助金额:
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10564014 - 财政年份:2022
- 资助金额:
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iSonogenetics for incisionless cell-type-specific neuromodulation of non-human primate brains
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- 批准号:
10655585 - 财政年份:2021
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$ 76.94万 - 项目类别:
The Role of Adaptor Protein Disabled-2 in Maintaining Endothelial Cell Function in Atherosclerosis
接头蛋白Disabled-2在维持动脉粥样硬化内皮细胞功能中的作用
- 批准号:
10391797 - 财政年份:2021
- 资助金额:
$ 76.94万 - 项目类别:
Molecular Mechanisms Governing Vascular Cell Function and Phenotype in Health and Disease
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- 批准号:
10600825 - 财政年份:2021
- 资助金额:
$ 76.94万 - 项目类别:
iSonogenetics for incisionless cell-type-specific neuromodulation of non-human primate brains
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- 批准号:
10270569 - 财政年份:2021
- 资助金额:
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10380102 - 财政年份:2021
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Focused ultrasound-enabled brain tumor liquid biopsy (FUS-LBx) supplement
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- 批准号:
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10318660 - 财政年份:2020
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