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：
8352133
负责人：
Katherine E Yutzey
金额：
$ 38.25万
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 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8352133
关键词：
Adult Age-Years Atherosclerosis Bicuspid 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 Stenosis Testing Therapeutic Therapeutic Intervention United States abstracting aortic valve aortic valve disorder aortic valve replacement base 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

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）：钙化性主动脉瓣疾病 (CAVD) 发生在超过 2% 的 65 岁以上人群中，通常会导致瓣膜狭窄，需要进行瓣膜置换术。 CAVD是一种进行性疾病，但CAVD进展的具体分子机制尚未明确，且CAVD进展的抑制剂尚未确定。目前，CAVD 尚无基于药物的治疗方法，需要新的 CAVD 治疗方法。 CAVD 通常发生在先天畸形或合并症的情况下，例如动脉粥样硬化和肾脏疾病。然而，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 进展有关，这些通路在心脏瓣膜和骨骼发育中也具有关键功能。然而，这些途径对 CAVD 的具体贡献以及它们之间的关系尚未确定。我们假设 BMP 和 Wnt 信号传导共同作用促进 CAVD 进展，并且抑制 BMP/pSmad1/5/8 信号传导将阻止或抑制体内 CAVD 进展。所提出的对培养瓣膜间质细胞中特定信号通路的操作、对人类外植患病主动脉瓣的分析以及对 CAVD 小鼠模型的治疗干预将用于识别目标信号通路并测试 CAVD 进展中的治疗策略。目的是： 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具有不同合并症的人类 CAVD 的钙化性疾病进展。 3) 确定 BMP 信号传导的抑制是否可以预防或抑制 CAVD 的 Klotho-null 模型中的钙质疾病进展。本研究的目的是确定调节 CAVD 进展的关键信号通路，并确定可有效治疗 CAVD 的瓣膜钙化药理学抑制剂。（摘要完）