MSX2-WNT SIGNALING IN CARDIOVASCULAR CALCIFICATION
心血管钙化中的 MSX2-WNT 信号传导
基本信息
- 批准号:8477231
- 负责人:
- 金额:$ 45.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2005
- 资助国家:美国
- 起止时间:2005-09-30 至 2015-05-31
- 项目状态:已结题
- 来源:
- 关键词:AgingAmputationApoptosisArteriesArteriolosclerosesArteriosclerosisAtherosclerosisBMP2 geneBlood VesselsBlood flowCalcifiedCalciumCardiacCardiovascular systemCellsChondrocytesChronic DiseaseCollagen Type IDataDiabetes MellitusDiabetic mouseDietDistalDown-RegulationElasticityElderlyEmbryoFatty acid glycerol estersFibrosisFundingGenesGeneticGenetic TranscriptionHealthHumanHypertensionInflammatoryLeadLifeLower ExtremityMediatingMediator of activation proteinMesenchymalMetabolicModelingMonkeberg&aposs Medial Calcific SclerosisMusMyocardialMyocardial InfarctionMyofibroblastNon-Insulin-Dependent Diabetes MellitusOsteoblastsOutcomeOxidative StressParathyroid Hormone ReceptorPerfusionPhenotypePhysiologicalPhysiologyPopulationProcessPropertyProteinsReactive Oxygen SpeciesRegulationRiskRoleSignal PathwaySignal TransductionSmooth Muscle MyocytesStreamStudy modelsTNF geneTechnologyTestingTherapeuticTissuesTransgenic MiceUp-RegulationUremiaValidationVascular Smooth MuscleVascular calcificationVesicleWNT Signaling PathwayWorkWorkloadboneburden of illnesscalcificationcrosslinkcytokinediabeticfeedingfootimpaired glucose toleranceimprovedin vivointerstitialmalemineralizationmouse modelosteogenicparacrineprogenitorprogramsresponsetranscription factor
项目摘要
DESCRIPTION (provided by applicant): Arteriosclerosis is the chronic disease state characterized by thickening and hardening of arterial walls with loss of elasticity. Atherosclerosis, Monckeberg's medial calcific sclerosis, and arteriolosclerosis are the three histopathologic types of arteriosclerosis. With advancing age, impaired glucose tolerance, diabetes, and hypertension, the conduit arteries become increasingly arteriosclerotic, losing compliance necessary for smooth distal tissue perfusion. This Windkessel physiology is impaired by changes in vascular geometry, and by changes in vascular matrix material properties arising from fibrosis, cross-linking and mineralization. Arteriosclerosis- viz., medial calcific sclerosis - has emerged as a particularly important contributor to lower extremity (LE) amputation risk in type II diabetes (T2DM). A better understanding of signaling pathways that control arterial fibrosis, calcification, and compliance will lead to new strategies for diminishing arteriosclerotic disease burden. Recent data identify Wnt/ 2 -catenin signaling and Wnt7 /LRP6 interactions as important in vascular calcification and tissue fibrosis -- down-stream of TNF-, BMP2-, and Msx2- activated osteogenic mineralization. Thus, the specific aims of this proposal are: Aim 1: "To establish the contributions of cell-autonomous vascular smooth muscle cell (VSMC) 2-catenin actions to vascular calcification and mural fibrosis in diabetic arteriosclerosis, using SM22- Cre(+);Ctnnb1(flox/+);LDLR(-/-) mice as a model for study." We test whether genetic down- regulation of VSMC 2-catenin signaling alters initiation and progression of diabetic arteriosclerosis, including diet-induced reductions in LE blood flow in the LDLR-/- mouse. Aim 2: "To examine the role of VSMC LRP6 expression in mediating the pro-calcific actions of Msx2-Wnt signaling during cardiovascular calcification, using diabetic SM22- Cre(+);LRP6(fl/fl);LDLR(-/-) mice as a model for study." LRP6 mediates Wnt7-dependent osteogenic and fibrotic signals in culture via 2-catenin and NFATc-mediated transcription. In this aim, we determine in vivo the cell-autonomous roles of VSMC LRP6 to the initiation of vascular calcification in diabetic arteriosclerosis in vivo, and the impact upon diet-induced activation of aortic osteogenic gene programs. The outcomes of these aims will provide physiological rationale and validation for reducing VSMC 2-catenin levels and LRP6 signaling as a potential therapeutic strategy to ameliorate vascular calcification -- and thus reduce lower extremity amputation risk in type II diabetes
描述(由申请人提供):动脉炎是一种慢性疾病状态,其特征是动脉壁增厚和硬化,失去弹性。动脉粥样硬化、Monckeberg's内侧钙化硬化和小动脉硬化是动脉硬化的三种组织病理学类型。随着年龄的增长,葡萄糖耐量受损,糖尿病和高血压,管道动脉变得越来越动脉化,失去了平滑远端组织灌注所必需的顺应性。这种Windkessel生理学受到血管几何结构变化以及纤维化、交联和矿化引起的血管基质材料性质变化的损害。动脉炎-即,中膜钙化硬化症-已成为II型糖尿病(T2 DM)下肢(LE)截肢风险的一个特别重要的因素。更好地理解控制动脉纤维化、钙化和顺应性的信号通路将导致减少动脉粥样硬化疾病负担的新策略。最近的数据表明,Wnt/ 2 -catenin信号传导和Wnt 7/LRP 6相互作用在血管钙化和组织纤维化中很重要--TNF-、BMP 2和Msx 2激活的成骨矿化的下游。因此,本提案的具体目的是:目的1:“使用SM 22- Cre(+); Ctnnb 1(flox/+);LDLR(-/-)小鼠作为研究模型,确定细胞自主的血管平滑肌细胞(VSMC)2-连环蛋白作用对糖尿病动脉硬化中血管钙化和壁纤维化的贡献。“我们测试VSMC 2-catenin信号的遗传下调是否改变糖尿病动脉硬化的起始和进展,包括LDLR-/-小鼠中饮食诱导的LE血流减少。目标二:“为了检查VSMC LRP 6表达在心血管钙化期间介导Msx 2-Wnt信号传导的促钙化作用中的作用,使用糖尿病SM 22- Cre(+); LRP 6(fl/fl);LDLR(-/-)小鼠作为研究模型。“LRP 6通过2-catenin和NFATc介导的转录在培养中介导Wnt 7依赖性成骨和纤维化信号。在这个目标中,我们确定在体内的VSMC LRP 6的细胞自主的作用,在体内糖尿病动脉硬化血管钙化的启动,并对饮食诱导的激活主动脉成骨基因程序的影响。这些目标的结果将为降低VSMC 2-catenin水平和LRP 6信号传导作为改善血管钙化的潜在治疗策略提供生理学原理和验证-从而降低II型糖尿病下肢截肢的风险
项目成果
期刊论文数量(1)
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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DWIGHT A. TOWLER其他文献
DWIGHT A. TOWLER的其他文献
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{{ truncateString('DWIGHT A. TOWLER', 18)}}的其他基金
Cdc42bpg signaling in arteriosclerosis and vascular fibrosis
动脉硬化和血管纤维化中的 Cdc42bpg 信号传导
- 批准号:
10448070 - 财政年份:2022
- 资助金额:
$ 45.95万 - 项目类别:
University of Texas Southwestern - Stimulating Access to Research in Residency (UT-StARR) Program
德克萨斯大学西南分校 - 促进住院医师研究 (UT-StARR) 计划
- 批准号:
10655275 - 财政年份:2021
- 资助金额:
$ 45.95万 - 项目类别:
Endocrine Regulation of Calcific Aortic Valve Sclerosis: PTH/PTHRP Receptor Signa
钙化性主动脉瓣硬化的内分泌调节:PTH/PTHRP 受体信号
- 批准号:
8597586 - 财政年份:2012
- 资助金额:
$ 45.95万 - 项目类别:
Endocrine Regulation of Calcific Aortic Valve Sclerosis: PTH/PTHRP Receptor Signa
钙化性主动脉瓣硬化的内分泌调节:PTH/PTHRP 受体信号
- 批准号:
8856647 - 财政年份:2012
- 资助金额:
$ 45.95万 - 项目类别:
Endocrine Regulation of Calcific Aortic Valve Sclerosis: PTH/PTHRP Receptor Signa
钙化性主动脉瓣硬化的内分泌调节:PTH/PTHRP 受体信号
- 批准号:
8535817 - 财政年份:2012
- 资助金额:
$ 45.95万 - 项目类别:
Endocrine Regulation of Calcific Aortic Valve Sclerosis: PTH/PTHRP Receptor Signa
钙化性主动脉瓣硬化的内分泌调节:PTH/PTHRP 受体信号
- 批准号:
8697129 - 财政年份:2012
- 资助金额:
$ 45.95万 - 项目类别:
Endocrine Regulation of Calcific Aortic Valve Sclerosis: PTH/PTHRP Receptor Signa
钙化性主动脉瓣硬化的内分泌调节:PTH/PTHRP 受体信号
- 批准号:
8352879 - 财政年份:2012
- 资助金额:
$ 45.95万 - 项目类别:
TNF-ALPHA AND BMP2-WNT SIGNALING IN DIABETIC VASCULAR DISEASE
糖尿病血管疾病中的 TNF-α 和 BMP2-WNT 信号转导
- 批准号:
7608622 - 财政年份:2008
- 资助金额:
$ 45.95万 - 项目类别:
TNF-ALPHA AND BMP2-WNT SIGNALING IN DIABETIC VASCULAR DISEASE
糖尿病血管疾病中的 TNF-α 和 BMP2-WNT 信号转导
- 批准号:
8020994 - 财政年份:2008
- 资助金额:
$ 45.95万 - 项目类别:
TNF-ALPHA AND BMP2-WNT SIGNALING IN DIABETIC VASCULAR DISEASE
糖尿病血管疾病中的 TNF-α 和 BMP2-WNT 信号转导
- 批准号:
7762246 - 财政年份:2008
- 资助金额:
$ 45.95万 - 项目类别:
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