Role of glycosaminoglycans (GAGs) in deep vein thrombus formation and resolution
糖胺聚糖(GAG)在深静脉血栓形成和消退中的作用
基本信息
- 批准号:10463067
- 负责人:
- 金额:$ 5.18万
- 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:2022-07-27 至 2026-07-26
- 项目状态:未结题
- 来源:
- 关键词:Academic Medical CentersAdhesionsAffectAgeAnimalsAntibodiesAnticoagulationAntithrombinsBindingBinding SitesBiomedical EngineeringBloodBlood PlateletsBlood VesselsBlood flowCCL2 geneCD14 geneCardiovascular DiseasesCathetersCause of DeathCell CommunicationCell ProliferationChondroitin SulfatesCoagulation ProcessCommunicationComplete Blood CountDataDeep Vein ThrombosisDevelopmentDiseaseDoctor of PhilosophyEndothelial CellsEnzymesEtiologyExhibitsFactor XIFactor XIaFibrinFibrinolytic AgentsFlow CytometryFunctional disorderGenesGlycocalyxGlycoproteinsGlycosaminoglycan Degradation PathwayGlycosaminoglycansGoalsHealth SciencesHematologyHemostatic functionHeparin Cofactor IIHeparitin SulfateHyaluronanImpairmentIn VitroIncidenceInferior vena cava structureInfiltrationInflammationInflammatoryInterleukin-1 betaInterleukin-13Intervention StudiesInvestigationLaboratoriesLeadershipMagnetic Resonance ImagingMeasuresMediator of activation proteinMembraneMentorshipModelingMusOperative Surgical ProceduresOregonPECAM1 genePathway interactionsPatientsPermeabilityPersonsPhenotypePhysiciansPlatelet ActivationPlatelet-Derived Growth FactorPlayPostoperative PeriodPostphlebitic SyndromePrednisoneProcessProteoglycanQuality of lifeRecurrenceResearch ProposalsResolutionRoleSalineScientistSenior ScientistSigns and SymptomsSmooth Muscle MyocytesStainsSurfaceTNF geneTechniquesThrombophiliaThrombosisThrombusTrainingTransforming Growth Factor betaUniversitiesVasodilationVeinsVenousWeightcareercareer developmentcell injuryconstrictiondeep veindesigndisabilityferumoxytolin vivoinjuredmacrophagemonocytemonolayermouse modelneutrophiloptimal treatmentsskillstherapeutic targetthrombolysisthromboticultrasoundvenous thromboembolism
项目摘要
PROJECT SUMMARY
Venous thromboembolism disorders represent the third most common cause of death from cardiovascular
disease. Despite the addition of catheter directed thrombolysis to standard anticoagulation therapy, recurrent
deep vein thrombosis (DVT) and subsequent post-thrombotic-syndrome (PTS), where the signs and symptoms
of DVT persist or worsen with thrombus resolution, still cause long term disability. Thus, a better understanding
of the basic mechanisms of DVT formation and resolution is needed.
In order for a DVT to form, endothelial cell (EC) injury must occur. Recently, the EC glycocalyx (eGCX), a
membrane bound mesh of glycoproteins, proteoglycans, and associated glycosaminoglycans (GAGs), has come
into focus as a multifunctional surface layer capable of regulating vasodilation, inflammation, proliferation, and
coagulation pathways. The 3 most prominent eGCX GAGs, heparan sulfate (HS), chondroitin sulfate (CS), and
hyaluronan (HA), have been associated with binding sites for anti-thrombin, heparin cofactor II, and non-
circulating factor XI (FXI). GAG binding of these critical coagulation components suggests an ambiguous
and currently unclarified role for GAGs in thrombus formation and resolution, warranting further
mechanistic investigation.
The goal of this proposal is to elucidate the mechanistic role by which the eGCX regulates DVT formation and
resolution. My hypothesis maintains that an injured eGCX will bolster DVT formation by increasing platelet-EC
interactions and activating the intrinsic clotting pathway, via release of non-circulating FXI. Furthermore, the
injured eGCX will impair DVT resolution by increasing inflammatory (M1) monocyte infiltration into the thrombus
and the vein wall. In Aim 1, I will determine the role of eGCX GAGs in platelet activation and thrombus formation
using a caval constriction DVT model in wildtype CD1 mice. In Aim 2, I will determine the role of eGCX GAGs
in causing post-thrombotic vein wall changes. This study will potentially identify relevant therapeutic targets that
directly affect DVT formation and resolution, paving the way for interventional studies and supporting the
rationale for the development of selective, safe, and effective antithrombotic agents. These studies will be
performed at Oregon's primary academic medical center, the Oregon Health and Science University in the
Departments of Biomedical Engineering and Vascular Surgery under the co-mentorship of Dr. Monica Hinds,
PhD and Dr. Khanh Nguyen, MD. The PI is supported by a mentorship team of senior scientists and physicians
with expertise in vascular pathophysiology, thrombosis, and vascular surgery. Career development activities
include training in mouse surgery, in vitro and in vivo analysis techniques, and coagulation and vascular
pathophysiology, as well as training in communication and leadership skills. This training is designed to support
the PI's career goals of becoming a physician-scientist with a long-term career goal of leading a productive and
translational vascular pathophysiology laboratory with a tightly integrated vascular surgery practice.
项目总结
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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Rick Mathews其他文献
Rick Mathews的其他文献
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{{ truncateString('Rick Mathews', 18)}}的其他基金
Role of glycosaminoglycans (GAGs) in deep vein thrombus formation and resolution
糖胺聚糖(GAG)在深静脉血栓形成和消退中的作用
- 批准号:
10700953 - 财政年份:2022
- 资助金额:
$ 5.18万 - 项目类别:
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