Propagation and Resolution of Injury in Calcific Aortic Valve Disease
钙化性主动脉瓣疾病损伤的传播和消退
基本信息
- 批准号:10216324
- 负责人:
- 金额:$ 44.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-15 至 2023-07-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnnexin A1Aortic Valve StenosisAreaBloodCMKLR1 geneCalcium ChannelCellsClinical ResearchDataDiseaseDisease ProgressionEnvironmentExperimental ModelsFamily suidaeGoalsHumanIn VitroInflammation MediatorsInjuryInterruptionInterventionInvestigationMechanicsMediator of activation proteinMedicalModelingMolecularMusPatternPhysiologicalPrevalencePreventive treatmentProcessPropertyResearchResearch SupportResolutionRiskRisk FactorsRoleSignal TransductionStenosisStructureSurfaceSyndromeTherapeuticTissuesTranslationsUp-RegulationVanilloidaortic valveaortic valve disordercalcificationcell injuryclinical translationclinically relevantdesigneffective therapyexperimental studyhemodynamicsin vivoin vivo Modelinnovationinterstitial cellmechanical forcemechanical loadmechanical propertiesmouse modelnovelpre-clinical researchreceptorresponseresponse to injurysensortissue injuryvalve replacement
项目摘要
Project Summary
Calcific aortic valve stenosis (CAVS) can be viewed as the end-stage of prolonged persistent injury in valve
tissue. Isolated valve interstitial cells (VICs), CAVS-prone mice, and humans with subclinical aortic valve
disease all demonstrate a propensity for propagation of injury in valve tissue, even after the initiating cause is
rectified. The goals of this proposal are understand mechanisms, and to identify therapeutic strategies with the
potential to inhibit or reverse propagation of injury in valve tissue. Early aortic valve disease entails thickening
and stiffening of valve cusps, and disruption of laminar shear at the blood-valve interface. The proposal will
address the hypothesis that tissue responses to altered mechanical forces may propagate a pattern of injury in
the aortic valve. Therefore, experiments proposed for Aim 1 will study modulation of signaling by the
mechano-responsive calcium channel, TRPV4, as a means to inhibit propagation of injury. In other disease
states, persistent tissue injury is characterized by sustained actions of mediators of inflammation, which may
be amenable to inhibition by specialized pro-resolving mediators (SPMs). New preliminary data indicate that
two SPMs are expressed in aortic valve cells, and that their expression is altered by CAVS-relevant conditions.
Experiments proposed for Aim 2 will study the impact of modulation of those two SPMs, annexin A1 and
chemokine-like receptor-1, upon propagation of injury in aortic valve cells. Both Aims will be pursued using
VICs grown on matrix with mechanical properties that can be manipulated to resemble properties of aortic
valves. Both Aims will be pursued using a mouse model that consistently develops CAVS, and which reaches
a state where amelioration of the initiating cause of CAVS no longer inhibits disease progression. These new
areas of research in aortic valve disease hold promise for translation to effective therapies for CAVS.
项目摘要
钙化性主动脉瓣狭窄(CAVS)是瓣膜长期持续性损伤的终末期
组织.分离的瓣膜间质细胞(VIC)、CAVS易感小鼠和患有亚临床主动脉瓣的人
疾病都表现出在瓣膜组织中传播损伤的倾向,即使在最初的原因是
纠正。该提案的目标是了解机制,并确定治疗策略,
抑制或逆转瓣膜组织损伤传播的潜力。早期主动脉瓣疾病需要增厚
以及瓣膜尖部的硬化和血液-瓣膜界面处的层流剪切的破坏。该提案将
解决组织对改变的机械力的反应可能传播损伤模式的假设,
主动脉瓣因此,针对目标1提出的实验将研究通过信号传导的调制。
机械响应性钙通道TRPV 4作为抑制损伤传播的手段。其他疾病
持续性组织损伤的特征是炎症介质的持续作用,
易于被专门的促消退介质(SPM)抑制。新的初步数据显示,
两种SPM在主动脉瓣细胞中表达,并且它们的表达被CAVS相关条件改变。
针对目标2提出的实验将研究这两种SPM(膜联蛋白A1和膜联蛋白A2)调节的影响
趋化因子样受体-1,在主动脉瓣细胞损伤的传播。这两个目标将通过以下方式实现:
在基质上生长的VIC具有可操纵以类似主动脉特性的机械特性
阀门.这两个目标都将使用一种小鼠模型来实现,该模型持续发展CAVS,
CAVS起始原因的改善不再抑制疾病进展的状态。这些新
主动脉瓣疾病的研究领域有望转化为CAVS的有效疗法。
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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ROBERT M WEISS其他文献
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{{ truncateString('ROBERT M WEISS', 18)}}的其他基金
Propagation and Resolution of Injury in Calcific Aortic Valve Disease
钙化性主动脉瓣疾病损伤的传播和消退
- 批准号:
10452547 - 财政年份:2018
- 资助金额:
$ 44.75万 - 项目类别:
Propagation and Resolution of Injury in Calcific Aortic Valve Disease
钙化性主动脉瓣疾病损伤的传播和消退
- 批准号:
9977238 - 财政年份:2018
- 资助金额:
$ 44.75万 - 项目类别:
Propagation and Resolution of Injury in Calcific Aortic Valve Disease
钙化性主动脉瓣疾病损伤的传播和消退
- 批准号:
9762207 - 财政年份:2018
- 资助金额:
$ 44.75万 - 项目类别:
Targeted siRNA nanotechnology for intravesical treatment of urologicaldiseases
靶向 siRNA 纳米技术用于膀胱内治疗泌尿系统疾病
- 批准号:
7938678 - 财政年份:2009
- 资助金额:
$ 44.75万 - 项目类别:
Targeted siRNA nanotechnology for intravesical treatment of urologicaldiseases
靶向 siRNA 纳米技术用于膀胱内治疗泌尿系统疾病
- 批准号:
7832079 - 财政年份:2009
- 资助金额:
$ 44.75万 - 项目类别:
Encapsulated siRNAs for treatment of urological disease
用于治疗泌尿系统疾病的封装 siRNA
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7481032 - 财政年份:2007
- 资助金额:
$ 44.75万 - 项目类别:
Encapsulated siRNAs for treatment of urological disease
用于治疗泌尿系统疾病的封装 siRNA
- 批准号:
7238990 - 财政年份:2007
- 资助金额:
$ 44.75万 - 项目类别:
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