Molecular and Cellular Mechanisms of Calcific Aortic Stenosis

说明(申请人提供)：钙化性主动脉瓣狭窄(CAVS)是最常见的需要外科瓣膜置换术的疾病。最近在人类患者中的研究表明，CAVS是一种涉及多个细胞过程的活跃的复杂综合征，而不是一种“老年”或“退行性”疾病。常见的心血管危险因素，包括年龄、性别、异常脂蛋白/胆固醇谱、高血压和II型糖尿病都与CAVD相关；然而，这种相关性在65岁以上的患者中很弱，他们进展为主动脉瓣狭窄的风险最大。相比之下，先天性瓣膜异常明显增加了风险。近一半的主动脉狭窄患者有二尖瓣(BAV)，这是最常见的先天性心脏畸形，影响0.6%的人口。值得注意的是，BAV患者在较早的年龄就出现了一种快速发展的CAVs，这表明遗传因素参与了这种疾病。然而，早期的CAVD患者是无症状的，不能用于人体研究，而对CAVD患者的后期研究不太可能揭示CAVD的潜在分子机制。为了填补这一空白，我们开发了人类骑兵的新型老鼠模型。该项目的总体目标是使用这些模型来表征调节主动脉瓣生物学和介导腔静脉的遗传途径。在这个项目中，我们将使用这些新的模型来检查EGFR、Notch1和NFATc1是否形成了一个维持主动脉瓣生物学的遗传网络，并在三个目标上调节了腔静脉。目标1将确定Notch1和EGFR信号在血管内皮细胞中是否相互作用，以维持内皮细胞的完整性。目标2将确定EGFR是否通过血管内皮细胞中的NFATc1保护瓣膜免受早期硬化。AIM 3将确定骑士队中涉及的Notch1、NFATc1和EGFR的常见下游效应器。由于它们在分化、存活和增殖中的核心作用，我们相信新发现的EGFR、Notch1和NFATc1之间的相互作用及其共同的下游靶点将为CAV的发病机制提供新的分子见解。这些信息将对开发这种最常见的瓣膜疾病的新治疗策略具有直接影响。

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.