Molecular and Cellular Mechanisms of Calcific Aortic Stenosis

描述（由申请人提供）：钙化性主动脉瓣狭窄（CAVS）是最常见的需要手术瓣膜置换术的疾病。最近对人类患者的研究表明，这不是一种“衰老”或“退行性”疾病；CAVS是一种涉及多个细胞过程的活动性复杂综合征。常见的心血管危险因素，包括年龄、性别、脂蛋白/胆固醇异常、高血压和II型糖尿病都与CAVD相关；然而，在65岁以上的患者中，这种相关性较弱，而65岁以上的患者进展为主动脉瓣狭窄的风险最大。相反，先天性瓣膜异常明显增加风险。近一半的主动脉狭窄患者患有双尖瓣主动脉瓣（BAV），这是最常见的先天性心脏畸形，占人口的0.6%。值得注意的是，BAV患者在更早的年龄发展为一种快速进展的CAVS，这表明遗传因素与该疾病有关。然而，早期CAVD患者无症状，无法进行人体研究，而晚期CAVD患者的研究不太可能揭示CAVS的潜在分子机制。为了填补这一空白，我们开发了新的人类CAVS小鼠模型。该项目的总体目标是利用这些模型来表征调节主动脉瓣生物学和介导CAVS的遗传途径。在本项目中，我们将使用这些新模型来检测Egfr、Notch1和Nfatc1是否形成一个遗传网络，以维持主动脉瓣的生物学并在三个目标中介导CAVS。目的1将确定Notch1和Egfr信号是否在VECs中相互作用以维持内皮的完整性。目的2将确定Egfr是否通过内皮细胞中的Nfatc1保护瓣膜免于早期硬化。目的3将确定与CAVS相关的Notch1、Nfatc1和Egfr的常见下游效应物。由于Egfr、Notch1和Nfatc1在分化、存活和增殖中的核心作用，我们相信新发现的Egfr、Notch1和Nfatc1及其共同的下游靶点之间的相互作用将为CAVS的发病机制提供新的分子见解。这些信息将对这种最常见的瓣膜疾病的新治疗策略的发展产生直接影响。

DESCRIPTION (provided by applicant): Calcific aortic valve stenosis (CAVS) is the most common disease needed surgical valve replacement. Recent studies in human patients indicate that, rather than a "senile" or "degenerative" disease; CAVS is an active complex syndrome involving multiple cellular processes. Common cardiovascular risk factors, including age, gender, abnormal lipoprotein/cholesterol profile, hypertension, and type II diabetes are all associated with CAVD; however, the association is weak in patients over 65 years old, who have the greatest risk of progressing to aortic valve stenosis. In contrast, congenital valve abnormalities markedly increase the risk. Nearly half of the patients with aortic stenosis have a bicuspid aortic valve (BAV), the most common congenital cardiac malformation affecting 0.6% of the population. Significantly, BAV patients develop a form of rapidly progressive CAVS at an earlier age, suggesting that genetic factors are involved in the disease. However, the patients with the early stages of CAVD are symptomless and unavailable for human studies, whereas the study of the latter stages of CAVD patients is unlikely to reveal the underlying molecular mechanisms of CAVS. To fill this gap, we have developed novel mouse models of human CAVS. The overall goal of this project is to use these models to characterize the genetic pathways that regulate aortic valve biology and mediate CAVS. In this program, we will use these new models to examine whether Egfr, Notch1, and Nfatc1 forms a genetic network that maintains the biology of the aortic valve and mediate CAVS in three Aims. Aim 1 will determine if Notch1 and Egfr signalings interact in the VECs to maintain endothelial integrity. Aim 2 will define if Egfr protects valve from early sclerosis through Nfatc1 in the VECs. Aim 3 will identify the common downstream effectors of Notch1, Nfatc1, and Egfr involved in CAVS. Because of their central roles in differentiation, survival, and proliferation, we believe that the newly identified interactions among Egfr, Notch1, and Nfatc1 and their common downstream targets will provide novel molecular insights into the pathogenesis of CAVS. The information would have direct implications in the development of new therapeutic strategies for this most common valve disease. PUBLIC HEALTH RELEVANCE: The goal of this project is to study cellular and molecular mechanisms of calcific aortic valve stenosis by using newly generated mouse models of the disease. Completion of the project will provide critical information on the underlying pathogenesis of human calcific aortic valve stenosis thereby helping develop new therapeutic and preventive strategies for this devastating human disease.