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

• 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
• 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

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>2%的65岁以上人群中，并且通常导致需要瓣膜置换的瓣膜狭窄。CAVD是一种进行性疾病，但CAVD进展的具体分子机制尚未明确，CAVD进展的抑制剂尚未确定。目前，还没有基于药物的CAVD治疗方法，需要新的CAVD治疗方法。CAVD通常发生在先天性畸形或合并症的背景下，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。对人类瓣膜的研究表明，BMP、Notch和Wnt信号通路参与了CAVD的进展，这些通路在心脏瓣膜和骨发育中也具有关键作用。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信号共同作用促进CAVD进展，并且BMP/pSmad 1/5/8信号的抑制将预防或抑制体内CAVD进展。所提出的在培养的瓣膜间质细胞中对特定信号传导通路的操作、对人类移植的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鉴定CAVD进展中的靶信号传导通路并测试治疗策略。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通路激活是否可预测具有不同合并症的人CAVD的钙化疾病进展。3)在Klotho无效CAVD模型中确定BMP信号传导的抑制是否预防或抑制钙化疾病进展。本研究的目的是确定调节CAVD进展的关键信号通路，并确定有效治疗CAVD的瓣膜钙化药理学抑制剂。 (End摘要）