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
• 负责人: ROBERT M WEISS
• 金额: $ 45.49万
• 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/9762207
• 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; LTB4R gene; 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; 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 钙化主动脉瓣狭窄（CAVS）可以看作是瓣膜长期持续损伤的最终阶段 组织。分离的瓣膜间质细胞（VIC），骑士易发小鼠和具有亚临床主动脉瓣的人类 疾病均表现出易于在瓣膜组织中传播损伤的倾向，即使引发原因是 纠正。该提案的目标是理解机制，并与 抑制瓣膜组织损伤的潜力。早期主动脉瓣疾病需要增厚 和瓣膜尖端的僵硬，以及在血阀界面处的层状剪切破坏。提案将 解决了组织对改变机械力的反应可能传播损伤模式的假设 主动脉瓣。因此，提出的针对AIM 1的实验将研究信号的调制 机械响应性钙通道TRPV4，作为抑制损伤传播的一种手段。在其他疾病中 各州，持续组织损伤的特征是炎症介体的持续作用，这可能 可以通过专门的促进介体（SPM）抑制。新的初步数据表明 两个SPM在主动脉瓣细胞中表达，并且它们的表达与骑士相关的条件改变。 提出的AIM 2的实验将研究这两个SPM的调节的影响，Annexin A1和 趋化因子样受体1，在主动脉瓣细胞损伤传播后。两个目标都将使用 在基质上生长的VIC具有机械性能，可以操纵以类似于主动脉的性质 阀。两种目标都将使用始终发展骑士并达到的鼠标模型来追求 改善骑士原因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骑士的有效疗法。