Cell Signaling Mechanisms of Calcific Aortic Valve Disease

钙化性主动脉瓣疾病的细胞信号传导机制

基本信息

批准号：
8880269
负责人：
Katherine E Yutzey
金额：
$ 37.68万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-23 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8880269
关键词：
Adult Age-Years Atherosclerosis Bone Development Cell Lineage Chronic Kidney Failure Clinical Data Comorbidity Congenital Abnormality Coronary Arteriosclerosis Disease Progression Etiology Goals Heart Valves Human Kidney Diseases Knockout Mice Modeling Molecular Morbidity - disease rate Mus Notch Signaling Pathway Notch and Wnt Signaling Pathway Osteogenesis Pathway interactions Patients Phosphorylation Population Prevention Progressive Disease Relative (related person)Signal Pathway Signal Transduction Testing Therapeutic Therapeutic Intervention United States abstracting aortic valve aortic valve disorder aortic valve replacement base bicuspid aortic valve bone cell calcification cohort effective therapy gene induction gene interaction in vivo inhibitor/antagonist interstitial cell mouse model notch protein novel therapeutic intervention osteogenic prevent response standard care valve replacement valvular stenosis

项目摘要

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)

描述（由申请人提供）：钙化主动脉瓣疾病（CAVD）发生在65岁以上的2％的人口中，并且经常导致瓣膜狭窄，因此需要更换瓣膜。 CAVD是一种进行性疾病，但是CAVD进展的特定分子机制尚未很好地定义，并且尚未确定CAVD进展的抑制剂。目前，没有针对CAVD的药理学治疗方法，需要针对CAVD的新治疗方法。 CAVD通常发生在先天性畸形或合并症的背景下，例如动脉粥样硬化和肾脏疾病。但是，尚不清楚特定的病原机制是否存在着不同病因的Cavd。对人植物瓣膜的研究牵涉到CAVD进展中的BMP，Notch和Wnt信号通路，这些途径在心脏瓣膜和骨骼发育中也具有关键功能。但是，这些途径对CAVD的具体贡献及其之间的关系尚未确定。我们假设BMP和WNT信号传导共同作用以促进CAVD进展，并且抑制BMP/PSMAD1/5/8信号传导将预防或抑制体内CAVD进展。在培养的瓣膜间隙细胞中，提出了对特定信号通路的操纵，对cavd小鼠模型中的人植体病态主动脉瓣的分析以及治疗干预措施将用于识别CAVD进展中的靶标信号传导途径和测试治疗策略。目的是：1）确定小鼠主动脉瓣间质细胞中成骨基因诱导中BMP和Wnt信号通路的相交。 2）确定BMP和WNT途径的激活是否可以预测具有不同合并症的人CAVD的钙化进展。 3）确定BMP信号的抑制是否阻止或抑制CAVD的Klotho-Null模型中的钙化疾病进展。这项研究的目标是定义调节CAVD进展的关键信号通路，并确定瓣膜钙化的药理学抑制剂，这是CAVD的有效治疗方法。（抽象的结尾）