Role of PTEN in Vascular Lesion Formation
PTEN 在血管病变形成中的作用
基本信息
- 批准号:8207875
- 负责人:
- 金额:$ 36.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-01-15 至 2012-12-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseActinsAffectAgonistAllelesAngioplastyAnti-Inflammatory AgentsAnti-inflammatoryArterial InjuryArterial IntimasAtherosclerosisAttenuatedAutocrine CommunicationAutomobile DrivingBiological ProcessBlood VesselsBone MarrowBone Marrow TransplantationCCL2 geneCD34 geneCXCL1 geneCXCL5 geneCause of DeathCell ProliferationCell WallCell physiologyCellsChemotactic FactorsCoculture TechniquesDataDevelopmentDown-RegulationEmbryonic DevelopmentEventExhibitsFamilyFunctional disorderGenetic RecombinationGerm LayersGrowthGrowth FactorHeart DiseasesHyperplasiaITGAM geneIn VitroInflammatoryInflammatory ResponseInjuryInterleukin-6InterventionKnockout MiceLabelLacZ GenesLeadLesionLinkLipidsMapsMedialMediatingMediator of activation proteinModelingMolecularMusMutant Strains MiceNuclear ReceptorsPTEN genePTEN proteinParacrine CommunicationPathogenesisPathway interactionsPhenotypePhosphoric Monoester HydrolasesPhysiologicalPlatelet-Derived Growth FactorProceduresProcessProductionProtein DephosphorylationProtein phosphatasePublishingRecruitment ActivityRegulationRelative (related person)Research DesignRoleSignal TransductionSmooth Muscle MyocytesSocietiesSpecificityStagingStem cellsStentsStromal Cell-Derived Factor 1SystemTechniquesTechnologyTestingTransplantationTumor Suppressor ProteinsUp-RegulationVascular remodelingWorkactivating transcription factorautocrinebasecell growthcell motilitychemokineclinically relevantcytokinehuman CXCL5 proteinhuman FRAP1 proteinhuman MYH11 proteinin vivoinhibitor/antagonistinjuredmigrationmonocyteneointima formationnovelparacrinepost interventionprogenitorprogramsprotective effectresponseresponse to injuryrestenosisrestorationtranscription factortumor progression
项目摘要
Restenosis is characterized by smooth muscle cell (SMC) accumulation in the arterial intima through
dedifferentiation, migration, and proliferation of medial-derived SMC. An inflammatory response, characterized
by bone marrow-derived and/or circulating inflammatory and progenitor cell recruitment to the injured vessel,
also contributes to restenosis. Several chemokines, including MCP-1/JE, SDF-1¿, IL-6, and CXCL1/KC, are
rapidly induced in SMC following injury and participate in the remodeling process through the recruitment of
inflammatory and vascular progenitor cells. Some of these factors have also been shown to directly affect the
biological function of the SMC itself placing the SMC as both a mediator and an effector of the injury response.
However, the underlying molecular programs activated in SMC in response to injury are not clearly defined.
Our previous work indicates SMC-specific PTEN inactivation, a negative regulator of PI3-kinase signaling, is
an early trigger driving vascular lesion formation. We generated inducible SMC-specific PTEN mutant mice
(PTEN iKO) and found that, compared to controls, PTEN iKO mice exhibit significant reductions of total PTEN
in major vessels with accompanying increased phosphoAkt levels and enhanced neointima formation following
carotid arterial injury. PTEN-deficient SMC in vitro exhibit an autocrine growth phenotype under basal
conditions and express a cytokine/chemokine profile similar to what is observed in SMC following experimental
injury. Preliminary data show that PTEN depletion activates the transcription factors, NF¿B and HIF-1¿;
inhibition of NF¿B or HIF-1¿ blocked the upregulation of specific chemokines mediated by PTEN depletion. On
the other hand, our preliminary data suggest that activation of the nuclear receptor, PPAR¿, in SMC
upregulates PTEN, therefore our studies will examine the ability of PPAR¿ activation to inhibit SMC
proliferation and regulate anti-inflammatory responses through the upregulation of SMC PTEN. Overall, our
preliminary data provide evidence that an alteration in SMC PTEN signaling serves as a key initiating
determinant driving pathological vascular remodeling through the production of a family of chemoattractants
that recruit inflammatory/progenitor cells through a paracrine mechanism and promote an autocrine SMC
hyperplastic response. Therefore, restoration of SMC PTEN signaling is anticipated to reverse the cascade of
events brought on by vascular injury. We will determine the consequences and mechanism of action of PTEN
loss on SMC production of progenitor/inflammatory cell mediators in cultured PTEN null SMC and assess the
relative contribution of SMC-specific deletion of PTEN in mice on chemokine-induced SMC hyperplasia and
recruitment of progenitor and inflammatory cells during neointima formation following experimental vascular
injury in Aim One. In Aim Two, we will determine the role of PPAR¿ agonists on the upregulation of PTEN and
biological functions of SMC and determine the role of PTEN regulation in mediating the protective effects of
PPAR¿ agonists against the development of injury-induced vascular remodeling.
再狭窄的特点是平滑肌细胞 (SMC) 在动脉内膜中积聚
内侧来源的 SMC 去分化、迁移和增殖。炎症反应,其特征是
通过骨髓来源的和/或循环的炎症和祖细胞募集到受伤的血管,
也有助于再狭窄。多种趋化因子,包括 MCP-1/JE、SDF-1¿、IL-6 和 CXCL1/KC
损伤后在 SMC 中迅速诱导,并通过招募
炎症和血管祖细胞。其中一些因素也已被证明直接影响
SMC 本身的生物学功能使 SMC 既作为损伤反应的介质又作为损伤反应的效应器。
然而,SMC 响应损伤而激活的潜在分子程序尚不清楚。
我们之前的工作表明 SMC 特异性 PTEN 失活(PI3 激酶信号传导的负调节因子)是
驱动血管病变形成的早期触发因素。我们生成了可诱导的 SMC 特异性 PTEN 突变小鼠
(PTEN iKO) 并发现,与对照组相比,PTEN iKO 小鼠的总 PTEN 显着减少
在主要血管中伴随着磷酸 Akt 水平升高和新内膜形成增强
颈动脉损伤。 PTEN 缺陷的 SMC 在体外表现出基础条件下的自分泌生长表型
条件下并表达与实验后在 SMC 中观察到的相似的细胞因子/趋化因子谱
受伤。初步数据表明,PTEN 缺失会激活转录因子 NF¿B 和 HIF-1 ;
抑制 NF?B 或 HIF-1? 可阻断 PTEN 耗竭介导的特定趋化因子的上调。在
另一方面,我们的初步数据表明,SMC 中核受体 PPAR¿ 的激活
上调 PTEN,因此我们的研究将检查 PPAR¿ 激活抑制 SMC 的能力
通过上调 SMC PTEN 来抑制增殖并调节抗炎反应。总体而言,我们的
初步数据提供证据表明 SMC PTEN 信号传导的改变是关键的启动因素
通过化学引诱剂家族的产生驱动病理性血管重塑的决定因素
通过旁分泌机制招募炎症/祖细胞并促进自分泌 SMC
增生反应。因此,恢复 SMC PTEN 信号传导有望逆转级联反应。
血管损伤引起的事件。我们将确定 PTEN 的后果和作用机制
培养的 PTEN 无效 SMC 中祖细胞/炎症细胞介质的 SMC 产生损失,并评估
小鼠中 SMC 特异性 PTEN 缺失对趋化因子诱导的 SMC 增生的相对贡献
实验血管后新内膜形成过程中祖细胞和炎症细胞的募集
在《目标一》中受伤。在目标二中,我们将确定 PPAR¿ 激动剂对 PTEN 和 PTEN 上调的作用
SMC 的生物学功能并确定 PTEN 调节在介导 SMC 保护作用中的作用
PPAR¿ 激动剂可对抗损伤引起的血管重塑的发展。
项目成果
期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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Mary Cm. Weiser-Evans其他文献
Mary Cm. Weiser-Evans的其他文献
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{{ truncateString('Mary Cm. Weiser-Evans', 18)}}的其他基金
PTEN promoter hypermethylation underlies vascular disease progression
PTEN 启动子高甲基化是血管疾病进展的基础
- 批准号:
10330591 - 财政年份:2021
- 资助金额:
$ 36.82万 - 项目类别:
PTEN promoter hypermethylation underlies vascular disease progression
PTEN 启动子高甲基化是血管疾病进展的基础
- 批准号:
10543851 - 财政年份:2021
- 资助金额:
$ 36.82万 - 项目类别:
PTEN-dependent regulation of SRF transcriptional activity and SMC phenotype control
SRF 转录活性的 PTEN 依赖性调节和 SMC 表型控制
- 批准号:
9247031 - 财政年份:2015
- 资助金额:
$ 36.82万 - 项目类别:
Reprogramming of mature smooth muscle cells to vascular progenitor cells
成熟平滑肌细胞重编程为血管祖细胞
- 批准号:
8967222 - 财政年份:2014
- 资助金额:
$ 36.82万 - 项目类别:
Microenvironmental Endogenous Reprogramming of Differentiated Smooth Muscle Cells
分化平滑肌细胞的微环境内源性重编程
- 批准号:
8451768 - 财政年份:2013
- 资助金额:
$ 36.82万 - 项目类别:
Microenvironmental Endogenous Reprogramming of Differentiated Smooth Muscle Cells
分化平滑肌细胞的微环境内源性重编程
- 批准号:
8666806 - 财政年份:2013
- 资助金额:
$ 36.82万 - 项目类别:
Role of PTEN in Hypoxia-Induced Vascular Remodeling, Raphael Nemenoff
PTEN 在缺氧诱导的血管重塑中的作用,Raphael Nemenoff
- 批准号:
7662790 - 财政年份:2009
- 资助金额:
$ 36.82万 - 项目类别:
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