Cell Signaling Mechanisms of Calcific Aortic Valve Disease

描述(由申请人提供)： 钙化性主动脉瓣病(CAVD)发生在65岁以上人群中的2%，经常导致瓣膜狭窄，需要进行瓣膜置换术。CAVD是一种进展性疾病，但CAVD进展的具体分子机制尚不清楚，CAVD进展的抑制物也尚未确定。目前，CAVD尚无基于药物的治疗方法，需要新的治疗方法。CAVD通常发生在先天性畸形或合并症的情况下，如动脉粥样硬化和肾脏疾病。然而，目前尚不清楚不同病因的CAVD是否存在特定的致病机制。对人类移植瓣膜的研究表明，BMP、Notch和Wnt信号通路与CAVD的进展有关，这些通路在心脏瓣膜和骨骼发育中也具有关键作用。然而，这些途径在CAVD中的具体作用以及它们之间的关系尚未确定。我们假设BMP和Wnt信号共同促进CAVD进展，抑制BMP/pSmad1/5/8信号通路将在体内阻止或抑制CAVD进展。所提出的对培养的瓣膜间质细胞中特定信号通路的操纵，对人类移植的病变主动脉瓣的分析，以及对CAVD小鼠模型的治疗干预，将被用于识别目标信号通路，并测试CAVD进展中的治疗策略。目的：1)确定BMP和Wnt信号通路在小鼠主动脉瓣间质细胞成骨基因诱导中的交叉点。2)确定BMP和Wnt通路激活是否可以预测伴有不同并发症的人CAVD的钙化疾病进展。3)确定抑制BMP信号是否可以阻止或抑制Klotho缺失的CAVD模型中钙化疾病的进展。这项研究的目标是确定调控CAVD进展的关键信号通路，并确定有效治疗CAVD的瓣膜钙化的药物抑制剂。 (摘要结束)

DESCRIPTION (provided by applicant): Calcific Aortic Valve Disease (CAVD) occurs in >2% of the population over 65 years of age and often leads to valvular stenosis that necessitates valve replacement. CAVD is a progressive disease, but the specific molecular mechanisms of CAVD progression are not well defined, and inhibitors of CAVD progression have not been identified. Presently, there are no pharmacologic-based treatments for CAVD, and new therapeutic approaches for CAVD are needed. CAVD often occurs in the context of congenital malformation or comorbidities, such as atherosclerosis and kidney disease. However, it is not known if specific pathogenic mechanisms occur with CAVD of distinct etiologies. Studies of human explanted valves have implicated BMP, Notch, and Wnt signaling pathways in CAVD progression, and these pathways also have critical functions in heart valve and bone development. However, the specific contributions of these pathways to CAVD and the relationships among them have not been determined. We hypothesize that BMP and Wnt signaling act together to promote CAVD progression and that inhibition of BMP/pSmad1/5/8 signaling will prevent or inhibit CAVD progression in vivo. The proposed manipulations of specific signaling pathways in cultured valve interstitial cells, analyses of human explanted diseased aortic valves, and therapeutic intervention in a mouse model of CAVD will be used to identify target signaling pathways and test therapeutic strategies in CAVD progression. The aims are: 1) Determine the intersection of BMP and Wnt signaling pathways in osteogenic gene induction in mouse aortic valve interstitial cells. 2) Determine if BMP and Wnt pathway activation is predictive of calcific disease progression in human CAVD with distinct comorbidities. 3) Determine if inhibition of BMP signaling prevents or inhibits calciic disease progression in the Klotho-null model of CAVD. The goals of this study are to define critical signaling pathways that regulate CAVD progression and to identify pharmacologic inhibitors of valve calcification that are effective treatments for CAVD. (End of Abstract)