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：
10452547
负责人：
ROBERT M WEISS
金额：
$ 44.36万
依托单位：
UNIVERSITY OF IOWA
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452547
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 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

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.

项目概要钙化性主动脉瓣狭窄（CAVS）可被视为瓣膜长期持续性损伤的终末期组织。离体瓣膜间质细胞 (VIC)、易发生 CAVS 的小鼠和患有亚临床主动脉瓣的人类所有疾病都表现出瓣膜组织损伤传播的倾向，即使在引发原因已确定之后也是如此。已纠正。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。早期主动脉瓣疾病导致增厚瓣膜尖端变硬，以及血液-瓣膜界面层流剪切力的破坏。该提案将解决了组织对改变的机械力的反应可能会传播损伤模式的假设主动脉瓣。因此，为目标 1 提出的实验将研究信号的调制机械响应钙通道 TRPV4 作为抑制损伤传播的手段。在其他疾病中指出，持续性组织损伤的特点是炎症介质的持续作用，这可能易于被专门的促解析介质 (SPM) 抑制。新的初步数据表明两种 SPM 在主动脉瓣细胞中表达，并且它们的表达会因 CAVS 相关条件而改变。为目标 2 提出的实验将研究这两个 SPM、膜联蛋白 A1 和主动脉瓣细胞损伤传播后的趋化因子样受体-1。这两个目标都将通过使用来实现 VIC 生长在具有机械特性的基质上，可以进行操作以模拟主动脉的特性阀门。这两个目标都将通过使用持续开发 CAVS 的小鼠模型来实现，并且达到 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（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Calcium Signaling Regulates Valvular Interstitial Cell Alignment and Myofibroblast Activation in Fast-Relaxing Boronate Hydrogels.

DOI：
10.1002/mabi.202000268
发表时间：
2020-12
期刊：
Macromolecular bioscience
影响因子：
4.6
作者：
Ma H;Macdougall LJ;GonzalezRodriguez A;Schroeder ME;Batan D;Weiss RM;Anseth KS
通讯作者：
Anseth KS

Acute effects of euglycemic-hyperinsulinemia on myocardial contractility in male mice.