The Role of The Thrombospondins In Intimal Hyperplasia
血小板反应蛋白在内膜增生中的作用
基本信息
- 批准号:9260484
- 负责人:
- 金额:$ 31.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-12-09 至 2020-11-30
- 项目状态:已结题
- 来源:
- 关键词:ADAMTS1 geneAddressAffectAmino Acid MotifsAnastomosis - actionAngioplastyAnimal ModelAnimalsArterial Fatty StreakArteriesBalloon AngioplastyBindingBiological AssayBiological AvailabilityBiologyBlood VesselsCD36 geneCD47 geneCell Surface ReceptorsCell physiologyCell-Matrix JunctionCessation of lifeChemotaxisClinicalCommon carotid arteryDataDevelopmentDigestionDiseaseDisintegrinsDown-RegulationEnzyme-Linked Immunosorbent AssayExtracellular MatrixExtracellular Matrix ProteinsFoundationsGene ExpressionGene TargetingGenesGoalsHyperplasiaIn VitroInjuryInterventionKnockout MiceKnowledgeLaboratoriesLeftLigationLimb structureLiteratureLongevityMediatingMessenger RNAMetalloproteasesMethodologyMethodsMicroRNAsMissionMolecularMolecular and Cellular BiologyMusMuscle CellsOperative Surgical ProceduresOutcomePathologyPatient CarePatientsPeptide HydrolasesPeripheralPeripheral arterial diseasePhysiologicalPolymerase Chain ReactionPopulationPositioning AttributePreventionProcessProteinsPublic HealthPublicationsQuality of lifeRNARNA BindingRattusRegulationResearchRoleSecondary toSignal PathwaySignal TransductionSmall Interfering RNASpecimenStaining methodStainsStructureSystemTechniquesTechnologyTestingTherapeuticThrombospondin 1ThrombospondinsTimeTissuesTranslationsTreatment EfficacyUnited States National Institutes of HealthUntranslated RNAVascular DiseasesVascular Smooth MuscleWestern BlottingWorkartery occlusionbasecell motilitycytokinedisabilityimprovedin vivoinnovationknock-downmigrationnovelpreventprotein expressionrestenosistherapeutic targetthrombospondin 2translational impactvascular smooth muscle cell proliferation
项目摘要
Restenosis secondary to intimal hyperplasia (IH) after balloon angioplasty to treat arterial blockages in
peripheral arteries is a significant cause of disability and death. The thrombospondins (TSPs) are
multifunctional matricellular proteins central to the development of intimal hyperplasia. They are not part of the
arterial wall structure, but exert their physiologic effects on arterial structure by binding cytokines, cell-surface
receptors, proteases and other proteins. This proposal focuses on three TSPs integral to the development of
intimal hyperplasia – TSP-1, TSP-2 and TSP-5. We have studied the effects of TSP-1 on vascular smooth
muscle cell (VSMC) proliferation and migration and its importance in the development of intimal hyperplasia;
however, increasing evidence exists that TSP-2 and TSP-5 have separate and contributory roles in this
pathology. All three TSPs are substrates of ADAMTS (A Disintegrin And Metalloproteinase with
Thrombospondin Motifs) proteins. ADAMTSs digest TSPs, enhancing or inhibiting TSP function, since the
fragments left after digestion have distinct effects themselves on intimal hyperplasia. Therefore, ADAMTS-1,-4,
and-7 will also be studied as they are involved in PAD and were also identified to be regulated by TSPs in our
prior VSMC gene study. Our long-term goal is to understand how TSPs can be manipulated therapeutically to
prevent intimal hyperplasia in vivo. The objective of this proposal is to determine how TSP-1, TSP-2 and TSP-5
specifically contribute to the development of intimal hyperplasia. Our central hypothesis is that the expression,
bioavailability, signaling pathways and changes in gene expression induced by TSP-1, TSP-2 and TSP-5 and
their interactions with ADAMTSs have distinct effects on regulating the development of IH. This hypothesis
was formulated on the basis of our strong preliminary data, our publications and the literature. The rationale for
the proposed project is that understanding the roles of TSPs on intimal hyperplasia will result in identification of
therapeutic targets to inhibit intimal hyperplasia and restenosis after balloon angioplasty. Our hypothesis will be
tested by pursuing the following Specific Aims: 1) determine the role that TSP-1, TSP-2 and TSP-5 each have
on intimal hyperplasia; 2) determine the differential effects of TSP-1, TSP-2 and TSP-5 on protein and
microRNA expression (i.e., miR-17~92 cluster), and their downstream effects on VSMC function; and 3)
establish the role of ADAMTSs in TSP-1, TSP-2 and TSP-5 activity and in the development of intimal
hyperplasia. The methodologies utilized to investigate these Specific Aims include: 1) modified Boyden
chamber to assess chemotaxis and colorimetric assay to assess for proliferation in VSMCs; 2) western blot,
ELISA and immunoPCR for cell signaling and protein expression; 3) quantitative real time polymerase chain
reaction for gene expression; 4) two animal models of intimal hyperplasia – common carotid artery balloon
injury in rats and ligation in mice; 5) use of knockout mice and siRNA for knockdown of TSP and ADAMTS
genes in vitro and in vivo to see effects on VSMCs and intimal hyperplasia, respectively; and 6) morphometric
analysis, western blot and immunohistochemical staining for analysis of arterial specimens. The siRNA work
will also involve testing our novel siRNAs directed at TSP/ADAMTS combinations that may prove to be a highly
effective method of blocking intimal hyperplasia at the time of angioplasty. The significance of the proposed
research is that the findings will provide a major advance toward identifying new strategies for preventing
restenosis due to intimal hyperplasia. The proposed research in this application is innovative, in our opinion,
because the findings will define the interactions of multiple TSPs and peptidases with TSP motifs (ADAMTSs)
in vascular disease and mechanisms through which these systems can be manipulated with novel siRNAs to
improve clinical outcomes. The findings from this application will advance efforts to improve quality of life and
longevity by providing safer and more effective therapeutic options for patients with peripheral arterial disease.
球囊血管成形术治疗动脉阻塞后继发内膜增生(IH)再狭窄
项目成果
期刊论文数量(0)
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Vivian Gahtan其他文献
Vivian Gahtan的其他文献
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{{ truncateString('Vivian Gahtan', 18)}}的其他基金
The Role of the Thrombospondins in Intimal Hyperplasia
血小板反应蛋白在内膜增生中的作用
- 批准号:
10044162 - 财政年份:2019
- 资助金额:
$ 31.5万 - 项目类别:
Thrombospondin-1, VSMC Migration and Intimal Hyperplasia - a role for statins
Thrombospondin-1、VSMC 迁移和内膜增生 - 他汀类药物的作用
- 批准号:
8458487 - 财政年份:2012
- 资助金额:
$ 31.5万 - 项目类别:
Thrombospondin-1, VSMC Migration and Intimal Hyperplasia - a role for statins
Thrombospondin-1、VSMC 迁移和内膜增生 - 他汀类药物的作用
- 批准号:
8698267 - 财政年份:2012
- 资助金额:
$ 31.5万 - 项目类别:
Thrombospondin-1, VSMC Migration and Intimal Hyperplasia - a role for statins
Thrombospondin-1、VSMC 迁移和内膜增生 - 他汀类药物的作用
- 批准号:
8795674 - 财政年份:2012
- 资助金额:
$ 31.5万 - 项目类别:
Thrombospondin-1, VSMC Migration and Intimal Hyperplasia - a role for statins
Thrombospondin-1、VSMC 迁移和内膜增生 - 他汀类药物的作用
- 批准号:
8334862 - 财政年份:2012
- 资助金额:
$ 31.5万 - 项目类别:
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