Propagation and Resolution of Injury in Calcific Aortic Valve Disease

项目摘要 钙化性主动脉瓣狭窄(CAVS)可视为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)、倾向于CAVS的小鼠和患有亚临床主动脉瓣的人 所有疾病都表现出在瓣膜组织中传播损伤的倾向，即使在启动原因是 已经改正了。这项建议的目标是了解机制，并确定治疗策略与 有可能抑制或逆转瓣膜组织中损伤的传播。早期的主动脉瓣疾病需要增厚 瓣膜尖端僵硬，血液-瓣膜界面层流剪切破坏。这项提议将 解决了这样的假设，即组织对改变的机械力的反应可能会在 主动脉瓣。因此，为目标1提出的实验将研究通过 机械反应钙通道，TRPV4，作为一种抑制损伤传播的手段。在其他疾病中 在美国，持续性组织损伤的特点是炎症介质的持续作用，这可能 要服从专门的亲解调停剂(SPM)的抑制。新的初步数据表明， 两个SPM在主动脉瓣细胞中表达，并且它们的表达被CAVS相关的条件改变。 为目标2提出的实验将研究这两个SPM，Annexin A1和Annexin A1的调制影响 趋化素样受体-1，当损伤在主动脉瓣细胞中传播时。这两个目标都将通过 VICs生长在具有机械性能的基质上，可以操纵成类似于主动脉的特性 阀门。这两个目标都将使用老鼠模型来实现，该模型不断发展骑士队，并达到 骑士队起病原因的改善不再抑制疾病发展的状态。这些新的 主动脉瓣疾病的研究领域有望转化为CAV的有效治疗方法。

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.