Glycocalyx Regeneration to Heal Vascular Inflammation and Atherosclerosis
糖萼再生治愈血管炎症和动脉粥样硬化
基本信息
- 批准号:10347882
- 负责人:
- 金额:$ 7.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-05 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAneurysmAnti-Inflammatory AgentsAnticoagulantsAntiplatelet DrugsArterial Fatty StreakArterial IntimasArteriesAspirinAtherosclerosisAttenuatedBindingBloodBlood VesselsBlood flowCardiovascular DiseasesCardiovascular systemCell CommunicationCell Culture TechniquesCell Surface ReceptorsCell physiologyCell surfaceCellsCellular InfiltrationChemicalsClinicalClinical TreatmentCommunicationComplexConfocal MicroscopyCore ProteinCoronary ArteriosclerosisDataDepositionDermatan SulfateDextransDiabetes MellitusDiseaseDyesEndothelial CellsEndotheliumEnvironmentEnzymesExhibitsExperimental DesignsFiltrationFormulationFoundationsFreeze SubstitutionFreezingFunctional disorderFutureGap JunctionsGlycocalyxGlycosaminoglycansGlypicanGoalsHealthHeparitin SulfateHumanHyaluronanInflammationInflammatoryKineticsLeadLeftLipidsLiquid substanceLow-Density LipoproteinsMechanicsMediatingMedicineModelingMolecularMorphologyMucous MembraneMyocardial InfarctionMyopathyNatural regenerationNitric Oxide SynthasePatientsPatternPeripheral Vascular DiseasesPermeabilityPharmaceutical PreparationsPhenotypePhysiologicalPlayPolysaccharidesPsychological reinforcementPublicationsRegulationReportingResearchRetinaRisk FactorsRoleSeveritiesShapesSphingosine-1-Phosphate ReceptorStrokeSystemTestingTherapeuticThickThinnessTranslatingTransmission Electron MicroscopyVascular DiseasesVascular PermeabilitiesWorkatherosclerosis riskbasecell behaviorclinical developmentefficacy testingendothelial dysfunctionendothelial repairexperimental studyglucuronyl glucosamine glycan sulfatehealingin vivoinnovationmechanotransductionmonocytenanomedicinenanoparticlenovelnovel therapeutic interventionnovel therapeuticspre-clinicalreceptorrepairedrestorationside effectsphingosine 1-phosphatestandard of caresugarsyndecantherapy developmentvascular inflammation
项目摘要
Project Summary: Atherosclerosis – a precursor to coronary artery disease and heart attack, stroke,
aneurysm, peripheral vascular disease, and retinal vascular disease – is a condition in which artery walls become
eroded, which makes them permeable to inflammatory lipids and cells that form disruptive plaques. Onset of
inflammation and atherosclerosis is recognized to coincide with inner blood vessel endothelium shedding of its
vasculoprotective glycocalyx coat. The glycocalyx is a sugar-rich layer that lines the inner blood vessel wall and
is largely composed of glycosaminoglycans, primarily heparan sulfate (HS) and hyaluronan. Glycocalyx loss
disables endothelium function and protection against unwanted molecular and cellular infiltration from the flowing
blood. At present, common cardiovascular medicines include lipid lowering and anti-platelet drugs. There is a
need for treatments that clinically restore endothelial glycocalyx to treat vascular disease, given that glycocalyx
integrity is at the front-line in combating atherosclerosis onset and progression. Recently, there has been new
development of therapies to promote glycocalyx health in order to reverse endothelium dysfunction,
inflammation, and atherosclerosis. Our research group is contributing to this effort by developing a novel
chemical formulation comprised of exogenous mucosal HS and sphingosine-1-phosphate (S1P). We previously
reported that this formulation can be used in cell culture experiments to repair degraded endothelial glycocalyx
and subsequently to restore transendothelial barrier function (Cheng et al., Int J Nanomedicine, 2016) and
interendothelial communication (Mensah et al., PLoS One, 2017). To our knowledge, we are the first group to
achieve functional glycocalyx regeneration in cultured endothelial cells. The envisioned project will build upon
our previous findings. We intend to further assess feasibility and perform mechanism-of-action studies in
endothelial cells cultured in a parallel plate chamber setting in which we can manipulate the fluid and/or chemical
environment to model pro-atherosclerotic conditions. This system has commonly been used to test the ability of
new drug treatments to mitigate dysfunction and pro-atherosclerotic risk factors in endothelial cells. In Aim 1,
we will conjugate, characterize, and optimize the exogenous HS and S1P formulation and test its efficacy and
mechanism-of-action in repairing damaged glycocalyx, in the onset of pro-atherosclerotic endothelial
dysfunction. Aim 2 will evaluate the ability of glycocalyx reinforcement to attenuate the severity of endothelium
hyper-permeability and other endothelial phenotype changes that occur in the early stages of atherosclerosis.
This work will lay the foundation for future preclinical in vivo studies and subsequent clinical efforts to further
develop the formulation and its utilization.
项目概述:动脉粥样硬化-冠状动脉疾病和心脏病发作,中风,
动脉瘤、外周血管疾病和视网膜血管疾病-是一种动脉壁变得
这使得它们可以渗透到形成破坏性斑块的炎症脂质和细胞中。发作
炎症和动脉粥样硬化被认为是与内血管内皮脱落相一致的,
保护血管的糖萼衣。糖萼是一种富含糖的层,排列在血管内壁上,
主要由糖胺聚糖组成,主要是硫酸乙酰肝素(HS)和透明质酸。糖萼丧失
使内皮功能丧失,
血目前常用的心血管药物包括降脂药和抗血小板药。有一个
需要临床上恢复内皮糖萼以治疗血管疾病的治疗,
完整性是对抗动脉粥样硬化发作和进展的第一线。最近,有新的
开发促进糖萼健康的疗法以逆转内皮功能障碍,
炎症和动脉粥样硬化。我们的研究小组正在通过开发一种新的
由外源性粘膜HS和鞘氨醇-1-磷酸(S1 P)组成的化学制剂。我们之前
报道,该制剂可用于细胞培养实验,以修复降解的内皮糖萼
并随后恢复跨内皮屏障功能(Cheng等,Int J Nanomedicine,2016)和
内皮间通讯(Mensah等,PLoS One,2017)。据我们所知,我们是第一批
在培养的内皮细胞中实现功能性糖萼再生。设想的项目将建立在
我们之前的发现我们打算进一步评估可行性,并进行作用机制研究,
内皮细胞培养在平行板室设置,其中我们可以操纵流体和/或化学物质,
环境来模拟促动脉粥样硬化状况。该系统通常用于测试
减轻内皮细胞功能障碍和促动脉粥样硬化危险因素的新药治疗。在目标1中,
我们将结合、表征和优化外源性HS和S1 P制剂,并测试其功效,
修复受损糖萼的作用机制,在促动脉粥样硬化内皮
功能障碍目的2评价糖萼强化减轻内皮损伤的能力
动脉粥样硬化早期出现的高渗透性和其他内皮表型变化。
这项工作将为未来的临床前体内研究和后续的临床工作奠定基础,以进一步
开发配方和应用。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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Eno Essien Ebong其他文献
Eno Essien Ebong的其他文献
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{{ truncateString('Eno Essien Ebong', 18)}}的其他基金
Glycocalyx Regeneration to Heal Vascular Inflammation and Atherosclerosis
糖萼再生治愈血管炎症和动脉粥样硬化
- 批准号:
10545041 - 财政年份:2022
- 资助金额:
$ 7.85万 - 项目类别:
Atheroprotective vs. Atherogenic Glycocalyx Mechanotransduction Mechanisms
动脉粥样硬化保护与致动脉粥样硬化糖萼机械转导机制
- 批准号:
9137702 - 财政年份:2015
- 资助金额:
$ 7.85万 - 项目类别:
Atheroprotective vs. Atherogenic Glycocalyx Mechanotransduction Mechanisms
动脉粥样硬化保护与致动脉粥样硬化糖萼机械转导机制
- 批准号:
9768526 - 财政年份:2015
- 资助金额:
$ 7.85万 - 项目类别:
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