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: 10216324
• 负责人: ROBERT M WEISS
• 金额: $ 44.75万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10216324
• 关键词: Address; Annexin A1; Aortic Valve Stenosis; Area; Blood; CMKLR1 gene; Calcium Channel; Cells; Clinical Research; Data; Disease; Disease Progression; Environment; Experimental Models; Family suidae; Goals; Human; In Vitro; Inflammation Mediators; Injury; Interruption; Intervention; Investigation; Mechanics; Mediator of activation protein; Medical; Modeling; Molecular; Mus; Pattern; Physiological; Prevalence; Preventive treatment; Process; Property; Research; Research Support; Resolution; Risk; Risk Factors; Role; Signal Transduction; Stenosis; Structure; Surface; Syndrome; Therapeutic; Tissues; Translations; Up-Regulation; Vanilloid; aortic valve; aortic valve disorder; calcification; cell injury; clinical translation; clinically relevant; design; effective therapy; experimental study; hemodynamics; in vivo; in vivo Model; innovation; interstitial cell; mechanical force; mechanical load; mechanical properties; mouse model; novel; pre-clinical research; receptor; response; response to injury; sensor; tissue injury; valve replacement

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。