Novel Approaches in Treatment of Vascular Injury Following Balloon Angioplasty
治疗球囊血管成形术后血管损伤的新方法
基本信息
- 批准号:8209987
- 负责人:
- 金额:$ 5.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-01-01 至 2013-12-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAdaptor Signaling ProteinAddressAdenovirusesAdultAffectAmericanAngioplastyArteriesAtherosclerosisBalloon AngioplastyBinding SitesBlood VesselsC-terminalCarotid ArteriesCatalytic DomainCause of DeathCell Culture TechniquesCell ProliferationCell SurvivalCell physiologyCellsDataDeveloped CountriesDevelopmentDiseaseDrug usageEndotheliumEventExtracellular MatrixFamilyFocal Adhesion Kinase 1Focal AdhesionsFutureGene TransferGoalsGrowth FactorHyperplasiaInjuryMediatingModalityModelingMutateMyocardial InfarctionNational Research Service AwardsPTK2 genePathogenesisPeripheral Vascular DiseasesPhosphotransferasesPlayProceduresProtein Tyrosine KinaseRattusRegulationResearch Project GrantsRoleRuptureSeriesSignal TransductionSmooth Muscle MyocytesStentsStrokeStructureTechniquesTestingTissuesTyrosineTyrosine PhosphorylationUnited StatesUp-RegulationVascular DiseasesVascular remodelingadenoviral-mediatedcell motilitydisabilityhuman BCAR1 proteinin vivoinhibitor/antagonistinjuredknock-downmigrationmortalitynovel strategiesoverexpressionprotein protein interactionprotein tyrosine kinase PYK2public health relevanceresearch studyresponserestenosisvascular smooth muscle cell migrationvascular smooth muscle cell proliferation
项目摘要
DESCRIPTION (provided by applicant): Atherosclerosis is the principal cause of myocardial infarction, stroke, and peripheral vascular disease, accounting for nearly half of all mortality in developed countries. Percutaneous transluminal angioplasty has become a well-established technique for revascularization of occluded arteries. However, the long-term efficacy of the procedure remains limited by progressive vessel renarrowing (restenosis) within the following few months after angioplasty. Abnormal vascular smooth muscle cell (VSMC) proliferation and migration is thought to play an important role in the pathogenesis of both atherosclerosis and restenosis. The stimulation of VSMC proliferation and migration requires signals arising from both growth factors and the extracellular matrix (ECM). The focal adhesion kinase family of nonreceptor protein tyrosine kinases (PTKs) - focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (PYK2) - play a central role in modulating VSMC signal transduction. The overall goal of this research project is to develop novel approaches in treatment of vascular injury following balloon angioplasty. The overall hypothesis of my NRSA application is that upregulation of FRNK, a naturally occurring inhibitor of FAK and PYK2, during vascular remodeling reduces smooth muscle cell migration and proliferation, and this occurs via multiple mechanisms. In Specific Aim 1, I will examine the temporal relationship between FAK, PYK2 and endogenous FRNK expression following balloon angioplasty. In Specific Aim 2, I will use adenoviral-mediated gene transfer to overexpress and "knock down" FRNK following balloon injury of the rat carotid artery, and analyze their effects on VSMC migration and proliferation in the arterial wall as well as analyze FAK and PYK2-mediated signal transduction. In Specific Aim 3, I will examine the role of FRNK localization and FRNK tyrosine phosphorylation in the inhibition of FAK and/or PYK2- dependent signaling, and FRNK's independent signaling function as compared to cells depleted of FAK. I believe that the questions addressed by this project have fundamental importance to our understanding of VSMC signaling. Future therapies for vascular remodeling in arterial diseases may include regulation of VSMC FRNK expression to selectively limit VSMC migration and proliferation without inhibition of beneficial endothelial function.
PUBLIC HEALTH RELEVANCE: Vascular diseases affect millions of Americans and are the leading cause of death and disability in the United States. I believe that the questions addressed by this project have fundamental importance to future therapies for vascular remodeling in arterial diseases such as atherosclerosis and restenosis.
描述(由申请人提供):动脉粥样硬化是心肌梗塞、中风和外周血管疾病的主要原因,占发达国家所有死亡率的近一半。经皮腔内血管成形术已成为闭塞动脉血运重建的成熟技术。然而,该手术的长期疗效仍然受到血管成形术后几个月内进行性血管再狭窄(再狭窄)的限制。血管平滑肌细胞(VSMC)异常增殖和迁移被认为在动脉粥样硬化和再狭窄的发病机制中发挥重要作用。 VSMC 增殖和迁移的刺激需要生长因子和细胞外基质 (ECM) 产生的信号。非受体蛋白酪氨酸激酶 (PTK) 的粘着斑激酶家族 - 粘着斑激酶 (FAK) 和富含脯氨酸的酪氨酸激酶 2 (PYK2) - 在调节 VSMC 信号转导中发挥核心作用。该研究项目的总体目标是开发治疗球囊血管成形术后血管损伤的新方法。我的 NRSA 应用的总体假设是,在血管重塑过程中,FRNK(FAK 和 PYK2 天然存在的抑制剂)的上调会减少平滑肌细胞迁移和增殖,并且这是通过多种机制发生的。在具体目标 1 中,我将检查球囊血管成形术后 FAK、PYK2 和内源性 FRNK 表达之间的时间关系。在具体目标2中,我将利用腺病毒介导的基因转移在大鼠颈动脉球囊损伤后过度表达和“敲低”FRNK,并分析它们对动脉壁中VSMC迁移和增殖的影响,以及分析FAK和PYK2介导的信号转导。在具体目标 3 中,我将研究 FRNK 定位和 FRNK 酪氨酸磷酸化在抑制 FAK 和/或 PYK2 依赖性信号传导中的作用,以及与耗尽 FAK 的细胞相比 FRNK 的独立信号传导功能。我相信这个项目解决的问题对于我们理解 VSMC 信号传导具有根本重要性。动脉疾病血管重塑的未来疗法可能包括调节 VSMC FRNK 表达,以选择性限制 VSMC 迁移和增殖,而不抑制有益的内皮功能。
公共卫生相关性:血管疾病影响着数百万美国人,是美国死亡和残疾的主要原因。我相信该项目解决的问题对于动脉粥样硬化和再狭窄等动脉疾病的血管重塑的未来治疗具有根本重要性。
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)
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Yevgeniya Emre Koshman其他文献
Yevgeniya Emre Koshman的其他文献
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{{ truncateString('Yevgeniya Emre Koshman', 18)}}的其他基金
Novel Approaches in Treatment of Vascular Injury Following Balloon Angioplasty
治疗球囊血管成形术后血管损伤的新方法
- 批准号:
8402612 - 财政年份:2011
- 资助金额:
$ 5.39万 - 项目类别:
Novel Approaches in Treatment of Vascular Injury Following Balloon Angioplasty
治疗球囊血管成形术后血管损伤的新方法
- 批准号:
7998985 - 财政年份:2011
- 资助金额:
$ 5.39万 - 项目类别: