Mechanisms of Congenital Heart Valve Disease
Mechanisms of Congenital Heart Valve Disease
批准号:
9905548
负责人:
Katherine E Yutzey
金额:
$48.39万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-07-01 至 2022-04-30
关键词:
AdultAffectAgeAllelesBirthCessation of lifeCharacteristicsCollagenCollagen FiberDNA Sequence AlterationDefectDiseaseDisease ProgressionElastinExhibitsExtracellular MatrixEyeFamily suidaeFibrillar CollagenFunctional disorderGene ExpressionGenesGlycosaminoglycansGoalsHeart Valve DiseasesHeart ValvesHeart failureHistologicHumanImpairmentIndividualInfiltrationInflammatoryKnockout MiceLeadLeftLeft Ventricular FunctionLesionLifeLive BirthMammalsMarfan SyndromeMedicalMitral ValveMitral Valve InsufficiencyModelingMolecularMorbidity - disease rateMorphologyMusMutationMyeloid CellsPathogenicityPathologicPharmacologyPopulationProteoglycanRegulatory PathwaySignal PathwaySignal TransductionSurgical ValvesTamoxifenTherapeuticTimeUnited StatesWNT Signaling Pathwayaortic valvebasebeta catenincell typeclinically relevantcomorbiditycytokinefilamingain of functionimprovedinducible gene expressioninterstitial cellmacrophagemouse modelnovel therapeuticspreventrepairedsingle-cell RNA sequencingskeletalstandard of carevalve replacement
中文摘要
先天性心脏瓣膜病的发病机制
项目摘要
由于形态学或细胞外基质(ECM)缺陷导致的先天性心脏瓣膜异常可
随着时间的推移进展为粘液瘤性瓣膜病(MVD),需要进行外科瓣膜置换术。MVD
影响高达2%的美国人口,超过10%的75岁以上的个体患有二尖瓣
返流程度目前,没有药物治疗,如果不治疗,MVD可导致左心室功能受损。
心室功能心力衰竭最终死亡目前的护理标准是瓣膜修复或
置换,具有高度侵入性,并非总是成功,耐久性有限,
年龄和许多常见的合并症。先天性瓣膜畸形,包括与
马凡氏综合征(MF)可发展为进行性MVD,其特征为胶原纤维断裂
并被粘多糖和蛋白聚糖替代,导致小叶增厚和功能不全。
然而,促进进行性瓣叶退化的机制尚不清楚,
目前尚无可用于预防或逆转MVD进展的疗法。我们最近在小鼠
MVD模型,包括马凡氏综合征的Fbn1C1039G模型,涉及Wnt信号传导和髓样细胞凋亡。
进行性MVD中细胞浸润。在Fbn1中具有基因编辑突变的猪也表明
MFS的特征,包括二尖瓣瓣叶增厚。我们假设先天性ECM
异常导致瓣膜间质细胞(维克)中Wnt信号传导增加,导致细胞因子
表达和巨噬细胞浸润,这有助于病理性胶原重塑和瓣膜
MVD进展特征性功能障碍。目的:1)鉴定维克细胞亚系、巨噬细胞
群体,以及小鼠、猪和人MFS瓣膜中MVD的基因表达变化。2)确定是否
Fbn1C1039G瓣膜中的Wnt信号传导是ECM失调和粘液瘤性疾病进展所必需的
疾病3)确定浸润性巨噬细胞是否有助于ECM的致病进展
MFS中的重塑和粘液瘤性瓣膜病。这些研究的长期目标是定义
MVD进展中的调节途径,包括先天性瓣膜缺陷导致的MVD,以及
确定新的MVD非手术治疗方法。
英文摘要
Mechanisms of Congenital Heart Valve Disease
Project Summary
Congenital heart valve abnormalities due to morphological or extracellular matrix (ECM) defects can
progress over time to myxomatous valve disease (MVD), necessitating surgical valve replacement. MVD
affects up to 2% of the US population and more than 10% of individuals over 75 have mitral valve
regurgitation. Currently, there is no medical therapy, and, if left untreated, MVD can lead to impaired left
ventricular function, heart failure, and ultimately death. The current standard of care is valve repair or
replacement, which is highly invasive, not always successful, of limited durability, and contraindicated by
age and many common comorbidities. Congenital valve abnormalities, including those associated with
Marfan Syndrome (MF) can develop into progressive MVD characterized by collagen fiber fragmentation
and replacement by mucopolysaccharides and proteoglycans, leading to leaflet thickening and insufficiency.
However, the mechanisms that promote progressive valve leaflet degeneration are not known, and there
are currently no therapies available to prevent or reverse MVD progression. Our recent studies in mouse
models of MVD, including the Fbn1C1039G model of Marfan syndrome, implicate Wnt signaling and myeloid
cell infiltration in progressive MVD. Pigs with gene-edited mutations in Fbn1 also demonstrate
characteristics of MFS, including thickening of mitral valve leaflets. We hypothesize that congenital ECM
abnormalities lead to increased Wnt signaling in valve interstitial cells (VIC)s, resulting in increased cytokine
expression and macrophage infiltration, that contribute to pathologic collagen remodeling and valve
dysfunction characteristic of MVD progression. The Aims are: 1) Identify VIC sublineages, macrophage
populations, and gene expression changes of MVD in mouse, pig and human MFS valves. 2) Determine if
Wnt signaling in Fbn1C1039G valves is required for ECM dysregulation and progression of myxomatous
disease. 3) Determine if infiltrating macrophages contribute to the pathogenic progression of ECM
remodeling and myxomatous valve disease in MFS. The long-term goals of these studies are definition of
regulatory pathways in MVD progression, including MVD resulting from congenital valve defects, and
identification of new nonsurgical therapeutic approaches for MVD.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Endothelial subpopulations in heart valve development and congenital heart disease
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批准号:10521286
-
项目类别:
-
资助金额:$48.51万
-
财政年份:2020
-
负责人:Katherine E Yutzey
-
依托单位:
Endothelial subpopulations in heart valve development and congenital heart disease
-
批准号:10319169
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项目类别:
-
资助金额:$48.51万
-
财政年份:2020
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负责人:Katherine E Yutzey
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依托单位:
Cell Signaling Mechanisms of Calcific Aortic Valve Disease
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批准号:8535811
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项目类别:
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资助金额:$36.41万
-
财政年份:2012
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负责人:Katherine E Yutzey
-
依托单位:
Cell Signaling Mechanisms of Calcific Aortic Valve Disease
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批准号:8697124
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项目类别:
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资助金额:$37.49万
-
财政年份:2012
-
负责人:Katherine E Yutzey
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依托单位:
Cell Signaling Mechanisms of Calcific Aortic Valve Disease
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批准号:8352133
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项目类别:
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资助金额:$38.25万
-
财政年份:2012
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负责人:Katherine E Yutzey
-
依托单位:
Cell Signaling Mechanisms of Calcific Aortic Valve Disease
-
批准号:8880269
-
项目类别:
-
资助金额:$37.68万
-
财政年份:2012
-
负责人:Katherine E Yutzey
-
依托单位:
The Akt-FoxO pathway in heart development
-
批准号:8208658
-
项目类别:
-
资助金额:$29.38万
-
财政年份:2011
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负责人:Katherine E Yutzey
-
依托单位:
The Akt-FoxO pathway in heart development
-
批准号:8148041
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项目类别:
-
资助金额:$29.09万
-
财政年份:2010
-
负责人:Katherine E Yutzey
-
依托单位:
Wnt signaling in heart valve development and disease
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批准号:8457110
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项目类别:
-
资助金额:$36.41万
-
财政年份:2009
-
负责人:Katherine E Yutzey
-
依托单位:
Wnt signaling in heart valve development and disease
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批准号:8628153
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项目类别:
-
资助金额:$37.49万
-
财政年份:2009
-
负责人:Katherine E Yutzey
-
依托单位:
Wnt signaling in heart valve development and disease
-
批准号:8290632
-
项目类别:
-
资助金额:$38.25万
-
财政年份:2009
-
负责人:Katherine E Yutzey
-
依托单位:
Wnt signaling in heart valve development and disease
-
批准号:8800566
-
项目类别:
-
资助金额:$37.68万
-
财政年份:2009
-
负责人:Katherine E Yutzey
-
依托单位:
Notch signaling in heart valve development and disease
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批准号:7557644
-
项目类别:
-
资助金额:$44.1万
-
财政年份:2009
-
负责人:Katherine E Yutzey
-
依托单位:
Notch signaling in heart valve development and disease
-
批准号:7851332
-
项目类别:
-
资助金额:$45.41万
-
财政年份:2009
-
负责人:Katherine E Yutzey
-
依托单位:
Regulation of Cardiac Growth by Akt-FoxO Signaling
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批准号:7429206
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项目类别:
-
资助金额:$32.9万
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财政年份:2007
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负责人:Katherine E Yutzey
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依托单位:
Twist1 regulation of valve progenitors
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批准号:8268986
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项目类别:
-
资助金额:$37.87万
-
财政年份:2006
-
负责人:Katherine E Yutzey
-
依托单位:
Twist1 regulation of valve progenitors
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批准号:7988328
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项目类别:
-
资助金额:$38.13万
-
财政年份:2006
-
负责人:Katherine E Yutzey
-
依托单位:
Twist1 regulation of valve progenitors
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批准号:8669794
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项目类别:
-
资助金额:$37.11万
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财政年份:2006
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负责人:Katherine E Yutzey
-
依托单位:
Tbx20 regulation of heart valve development
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批准号:7617207
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项目类别:
-
资助金额:$36.41万
-
财政年份:2006
-
负责人:Katherine E Yutzey
-
依托单位:
Twist1 regulation of valve progenitors
-
批准号:8468726
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项目类别:
-
资助金额:$36.05万
-
财政年份:2006
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负责人:Katherine E Yutzey
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依托单位:
海外基金