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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：
8535811
负责人：
Katherine E Yutzey
金额：
$ 36.41万
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/8535811
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）：