Mouse Model of Human Calcific Aortic Valve Stenosis

说明(申请人提供)：钙化性主动脉瓣狭窄(CAVS)是美国外科瓣膜置换最常见的适应症，需要瓣膜成形术或外科置换。多年来，CAVS一直被认为是一种被动的退行性过程，但最近对人类患者进行的研究的数据积累改变了这一范式，表明它是一种涉及多个主动细胞过程的复杂综合征。目前的假说是，主动脉瓣叶内皮屏障的破坏是导致钙化瓣膜的一连串炎症和退变过程的早期病理事件。然而，需要新的骑兵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预防疾病进展的新型非侵入性治疗提供潜在的靶点。在这里，我们建议建立一种新的小鼠模型，该模型不仅可以完全再现人类Cavs的病理，而且可以从机械上解决早期瓣膜内皮损伤以及随后的炎症和退变过程。利用一种新的瓣膜内皮细胞特异性Cre小鼠品系和一种条件性EGFR小鼠品系，通过基因干扰瓣膜内皮细胞中的EGFR基因，建立小鼠CAVS模型。我们将利用转录图谱和RNA干扰来描述CAV的病理特征，并识别与内皮损伤、炎症和退变有关的分子变化。在本研究的结论中，我们将建立和表征一个新的CAVS小鼠模型，为进一步研究CAVS的发病机制和寻找治疗这种常见的破坏性人类疾病的药物靶点奠定基础。 公共卫生相关性：本项目的目标是建立一种新的钙化性主动脉瓣狭窄小鼠模型，以研究其潜在的发病机制。该项目的完成将有助于为这一毁灭性的人类疾病制定新的治疗和预防战略。

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.