Advanced Non-invasive Imaging in the Investigation of Aortic Stenosis Pathobiology
主动脉瓣狭窄病理学研究中的先进无创成像
基本信息
- 批准号:10693935
- 负责人:
- 金额:$ 72.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:ADAMTSAccelerationAcetylcysteineAdhesionsAffectAgeAge YearsAnimal ModelAnimalsAntioxidantsAortaAortic Valve StenosisArteriogramAtherosclerosisBindingBiologyBloodBlood PlateletsBlood VesselsCardiac DeathCell ProliferationClinical TrialsCountryDataDependenceDevelopmentDiseaseDisease ProgressionDoppler EchocardiographyDoppler UltrasoundEchocardiographyElderlyEndothelial CellsEndotheliumEvaluationEventGenerationsGoalsGrowth FactorGuidelinesHealth ExpendituresHeartHeart ValvesHeart failureHistologicHistologyHumanImageInflammatoryInterventionInvestigationLeftLeft Ventricular FunctionLeft Ventricular HypertrophyLeft Ventricular MassLeft Ventricular RemodelingLigandsLongitudinal StudiesLow-Density LipoproteinsMediatingMediatorMedicalMethodsModelingMolecular ConformationMusOperative Surgical ProceduresPDGFA genePathway interactionsPatientsPatternPeptide HydrolasesPhenotypePlasmaPlatelet-Derived Growth FactorPopulationPredictive FactorProceduresProcessProliferatingProteolysisRANTESReactive Oxygen SpeciesRecombinantsResearchResistanceResourcesSclerosisSecondary toSignal PathwaySignal TransductionSignaling MoleculeSurfaceSystems BiologyTechniquesTestingTissuesVentricularWild Type Mouseacetovanilloneaggressive therapyaortic valveaortic valve replacementblood pumpcalcificationcell transformationcontrast enhancedcytokineelectric impedanceextracellular vesicleshemodynamicshigh riskhypertension treatmentin vivoindexinginhibitorinterstitial cellmolecular imagingmouse modelnon-compliancenon-invasive imagingnoninvasive diagnosisnovelosteogenicparacrinepharmacologicpreventprospectiverecruittherapeutic targettranscriptomicsultrasoundvalve replacementvon Willebrand Factor
项目摘要
SUMMARY
Aortic stenosis (AS) is a serious condition that affects 2-4% of the elderly, and is responsible for U.S. healthcare
expenditures of over $6 billion annually attributable mostly to valve replacement procedures. Frequently, AS is
diagnosed by non-invasive imaging before it is severe or symptomatic. Yet there are no pharmacologic therapies
to slow progression of disease. The pathobiology of AS involves the myofibroblastic and osteoblastic
transformation of valvular interstitial cells (VICs) that mediate matrix remodeling and calcification. The plurality
of events and signaling pathways that influence VICs is one reason for lack of effective medical therapy. Using
in vivo molecular imaging of the aortic root and comprehensive echocardiography, we have found that mice that
lack the ability to cleave von Willebrand Factor (VWF) multimers from the endothelial surface develop
progressive AS and load-related left ventricular hypertrophy. Valve leaflets from these animals demonstrate
endothelial adhesion of platelets and platelet extracellular vesicles, and also typical patterns of VIC proliferation
and transformation. These findings are consistent with the idea that platelets contribute to AS by binding VWF
and acting in a juxtracrine fashion through local release of platelet-derived growth factors, cytokines, and reactive
oxygen species (ROS) which are known to stimulate VIC transformation. Accordingly, inhibiting platelet
interaction with VWF at the valve endothelial surface could prevent the activation of many parallel signaling
pathways that contribute to AS. Our overall goal is to integrate non-invasive imaging with histology,
transcriptomics, and blood markers to characterize this potentially treatable mechanism for AS. In Aim 1, we will
provide definitive evidence that platelet adhesion contributes to AS by longitudinal assessment of mice deficient
for the ADAMTS13 protease that cleaves shear-activated VWF from the endothelial surface. We will investigate
whether deletion of platelet GPIb, the counterligand for VWF; and treatment with recombinant ADAMTS13.
Because platelet-endothelial adhesion also contributes to vascular stiffness, a systems-biology approach will be
used with non-invasive imaging of arterial compliance, LV remodeling, and load-dependent indices of LV
function. In Aim 2, we will test whether novel pharmacologic approaches that reduce excess endothelial-
associated VWF multimers suppress the development of AS and LV remodeling in the murine models. Therapies
will include (i) n-acetylcysteine which inhibits VWF self-association, and (ii) an acetovanillone inhibitor of Nox2
which reduces the generation of ROS and, consequently, excess endothelial-associated VWF. In Aim 3, a proof-
of-concept prospective clinical trial will be performed in patients with mild or moderate AS to determine whether
blood markers of abnormal VWF proteolysis and platelet-derived signaling factors predict rapidly progressive AS
and arterial non-compliance. These data will be integrated with novel echocardiographic features of valve shear
based on the known shear-dependency of “opening” of the otherwise cryptic VWF A1 domain for platelet GPIb
binding and shear-related transcriptomic control of platelet signaling molecules
摘要
主动脉狭窄(AS)是一种严重的疾病,影响2%-4%的老年人,并对美国的医疗保健负责
每年超过60亿美元的支出,主要归因于瓣膜更换程序。通常,就像现在一样
在病情严重或有症状之前,通过非侵入性成像进行诊断。然而,目前还没有药物疗法。
延缓疾病的发展。AS的病理生物学涉及肌成纤维细胞和成骨细胞
参与基质重塑和钙化的瓣膜间质细胞(VIC)的转化。多数人
影响VICS的事件和信号通路的缺失是缺乏有效药物治疗的原因之一。vbl.使用
在活体分子成像的主动脉根部和全面的超声心动图,我们发现,小鼠
缺乏从内皮细胞表面切割von Willebrand因子(VWF)多聚体的能力
进行性动脉粥样硬化和负荷性左心室肥厚。这些动物的瓣叶证明了
血小板和血小板胞外小泡的内皮黏附以及VIC增殖的典型模式
和转型。这些发现与血小板通过结合VWF促进AS的观点是一致的。
并通过局部释放血小板衍生生长因子、细胞因子和反应性细胞因子而发挥旁分泌作用
已知能刺激VIC转化的氧物种(ROS)。相应地,抑制血小板
与VWF在瓣膜内皮细胞表面的相互作用可以阻止许多平行信号的激活
导致动脉粥样硬化的途径。我们的总体目标是将非侵入性成像与组织学相结合,
转录学和血液标记物来表征这一潜在的AS治疗机制。在目标1中,我们将
通过对缺陷小鼠的纵向评估,提供明确的证据表明,血小板黏附有助于AS
对于从内皮细胞表面切割剪切激活的VWF的ADAMTS13蛋白酶。我们会调查的
是否删除vWF的反配体--血小板GPIB;以及用重组ADAMTS13治疗。
由于血小板-内皮细胞黏附也会导致血管僵硬,系统生物学方法将是
用于动脉顺应性、左室重构和负荷相关指数的无创性成像
功能。在目标2中,我们将测试减少过度内皮细胞的新药理学方法-
相关的VWF多聚体抑制AS和LV在小鼠模型中的重构。治疗方法
将包括(I)抑制VWF自结合的N-乙酰半胱氨酸,以及(Ii)NOX2的乙酰香草酮抑制剂
这减少了ROS的产生,从而减少了过量的内皮相关VWF。在《目标3》中,有一个证据-
将在轻度或中度患者中进行概念外前瞻性临床试验,以确定
VWF蛋白分解和血小板衍生信号因子异常的血液标志物预测快速进展性AS
和动脉不顺应性。这些数据将与瓣膜剪切的新超声心动图特征相结合。
基于已知的血小板GPIB的VWF A1结构域“打开”的剪切力依赖性
血小板信号分子的结合和剪切相关转录调控
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)
专利数量(0)
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Jonathan R Lindner其他文献
1074-155 The severity of peripheral vascular disease can be assessed by skeletal muscle contrast-enhanced ultrasound
- DOI:
10.1016/s0735-1097(04)91391-5 - 发表时间:
2004-03-03 - 期刊:
- 影响因子:
- 作者:
Thanjavur K Bragadeesh;Antionio Micari;marco Pascotto;Ibrahim Sari;Sanjiv Kaul;Jonathan R Lindner - 通讯作者:
Jonathan R Lindner
1074-152 Will combinations of multiple agents produce more robust contrast imaging? An in vitro study and in vivo studies in dogs
- DOI:
10.1016/s0735-1097(04)91388-5 - 发表时间:
2004-03-03 - 期刊:
- 影响因子:
- 作者:
Xiaokui Li;Hui Jiang;Diane Paine;Zuhua Mao;Aarti Hejmadi Bhat;Rima S Bader;Patrick von Behren;David Gustafson;Jonathan R Lindner;Alexander L Klibanov;David J Sahn - 通讯作者:
David J Sahn
Jonathan R Lindner的其他文献
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{{ truncateString('Jonathan R Lindner', 18)}}的其他基金
Advanced Non-invasive Imaging in the Investigation of Aortic Stenosis Pathobiology
先进的无创成像在主动脉瓣狭窄病理学研究中的应用
- 批准号:
10522099 - 财政年份:2022
- 资助金额:
$ 72.18万 - 项目类别:
Augmentation of Tissue Perfusion in PAD with Ultrasound-mediated Cavitation
超声介导的空化增强 PAD 中的组织灌注
- 批准号:
9258481 - 财政年份:2016
- 资助金额:
$ 72.18万 - 项目类别:
Augmentation of Tissue Perfusion with Ultrasound-mediated Cavitation
用超声介导的空化增强组织灌注
- 批准号:
10379090 - 财政年份:2016
- 资助金额:
$ 72.18万 - 项目类别:
Augmentation of Tissue Perfusion with Ultrasound-mediated Cavitation
用超声介导的空化增强组织灌注
- 批准号:
10592406 - 财政年份:2016
- 资助金额:
$ 72.18万 - 项目类别:
Augmentation of Tissue Perfusion in PAD with Ultrasound-mediated Cavitation
超声介导的空化增强 PAD 中的组织灌注
- 批准号:
9005245 - 财政年份:2016
- 资助金额:
$ 72.18万 - 项目类别:
Augmentation of Tissue Perfusion with Ultrasound-mediated Cavitation
用超声介导的空化增强组织灌注
- 批准号:
10188594 - 财政年份:2016
- 资助金额:
$ 72.18万 - 项目类别:
Augmentation of Tissue Perfusion with Ultrasound-mediated Cavitation
用超声介导的空化增强组织灌注
- 批准号:
10650238 - 财政年份:2016
- 资助金额:
$ 72.18万 - 项目类别:
MOLECULAR IMAGING OF INFLAMMATION IN ATHEROSCLEROSIS
动脉粥样硬化炎症的分子成像
- 批准号:
8357882 - 财政年份:2011
- 资助金额:
$ 72.18万 - 项目类别:
CONTRAST ULTRASOUND ASSESSMENT OF MICROVASCULAR FUNCTION IN INSULIN RESISTANT
超声造影对胰岛素抵抗患者微血管功能的评估
- 批准号:
8357883 - 财政年份:2011
- 资助金额:
$ 72.18万 - 项目类别:
Molecular Imaging of Ischemic Memory with Ultrasound - Transition to Humans
超声对缺血性记忆的分子成像 - 应用于人类
- 批准号:
7838481 - 财政年份:2009
- 资助金额:
$ 72.18万 - 项目类别:
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