Mouse Model of Human Calcific Aortic Valve Stenosis

描述（由申请人提供）：钙化性主动脉瓣狭窄（CAVS）是美国最常见的手术瓣膜置换术指征，需要瓣膜成形术或手术置换术。多年来，CAVS一直被认为是一种被动的退行性过程，但最近对人类患者的研究积累的数据已经改变了这种范式，表明它是一种涉及多个活跃细胞过程的复杂综合征。目前的假设是，主动脉瓣小叶内皮屏障的破坏是引发炎症级联反应和退行性过程导致钙化瓣的早期病理事件。然而，需要新的CAVS动物模型来验证这一假设。此外，更好地了解瓣膜内皮损伤的分子机制及其后果可能为防止疾病进展的新型非侵入性治疗提供潜在靶点。在这里，我们建议建立一个新的小鼠模型，不仅可以完全重现人类CAVS的病理，而且还允许我们从机制上解决早期瓣膜内皮损伤和随后的炎症和退行性过程。该小鼠CAVS模型将使用一种新型的瓣膜内皮特异性Cre小鼠系和一种条件固定EGFR小鼠系，通过基因破坏瓣膜内皮中的EGFR基因来产生。我们将描述CAVS的病理特征，并利用转录谱分析和RNA干扰识别导致内皮损伤、炎症和变性的分子改变。在本研究结束时，我们将生成并表征一种新的CAVS小鼠模型，以进一步研究CAVS的发病机制，并确定这种常见的破坏性人类疾病的药物靶点。

DESCRIPTION (provided by applicant): Calcific aortic valve stenosis (CAVS) is the most common indication for surgical valve replacement in the United States, requiring valvuloplasty or surgical replacement. CAVS has been thought for years as a passive degenerative process, but accumulating data from recent studies of human patients have shifted the paradigm by suggesting that it is a complex syndrome involving multiple active cellular processes. The current hypothesis is that disruption of the endothelial barrier of aortic valvular leaflets is the early pathological event triggering a cascade of inflammation and degenerative processes leading to calcific valves. New animal models of CAVS, however, are needed to test this hypothesis. Moreover, better understanding of molecular mechanisms of valvular endothelial damage and its consequence may provide a potential target for novel non- invasive therapies that prevents disease progression. Here, we propose to build a new mouse model that not only can fully recapture the pathology of human CAVS but also allow us to address mechanistically the early valvular endothelial injury and subsequent inflammation and degenerative processes. This mouse CAVS model will be generated by genetically disrupt EGFR gene in the valvular endothelium using a novel valvular endothelial specific Cre mouse line and a conditional floxed EGFR mouse line. We will characterize the pathology of CAVS and identify molecular alterations responsible for endothelial injury, inflammation, and degeneration using transcriptional profiling and RNA interference. At the conclusion of this study, we will have generated and characterized a novel mouse model of CAVS for further studying the pathogenesis of CAVS and identifying for drug targets for this common devastating human disease. PUBLIC HEALTH RELEVANCE: The goal of this project is to build a new mouse model of calcific aortic valve stenosis to study the underlying pathogenesis. Completion of this project will help to develop new therapeutic and preventive strategies for this devastating human disease.