Cellular signaling events in the pathogenesis of arterial stiffening: an approach to identify Cbfa1 (core binding factor alpha1) as a key mediator of vascular remodeling

动脉硬化发病机制中的细胞信号事件：识别 Cbfa1（核心结合因子 α1）作为血管重塑关键介质的方法

• 批准号: 209947703
• 负责人: Privatdozent Dr. Uwe Raaz
• 金额: --
• 依托单位: Division of Cardiovascular Medicine
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/209947703?language=en
• 关键词: Cellular; signaling; events; pathogenesis; arterial

Arterial stiffening is associated with ageing and numerous disease states such as hypertension, congestive heart failure, diabetes mellitus or renal failure. Here arterial stiffness may represent a central pathophysiologic factor that alters/impairs macro- and microcirculation resulting in disease progression. In accordance increased arterial stiffness has been identified as an independent risk factor for cardiovascular disease. Consequently modulation of arterial stiffness represents an attractive therapeutic target for a plenty of diseases. However, effective therapies that target the structural abnormalities and changes in vascular signaling that underlie the process of stiffening are currently lacking.Vascular remodeling (i.e. the structural correlate of arterial stiffening) comes along with an altered pattern of gene expression and activation of specific cellular signaling pathways. Preliminary data indicate a critical role of the transcription factor, core binding factor alpha1 (Cbfa1) as a mediator of arterial stiffening.This project is based on the assumption that Cbfa1 is a universal regulator of vascular fibrosis and arterial stiffening. The aim of this project therefore is to test the hypotheses that 1) arterial Cbfa1 expression is commonly induced by diverse triggers of vascular stiffening (e.g., mechanical stress, hormones as angiotensin II or insulin, glucose, etc.), 2) enhanced Cbfa1 activity, per se, results in increased vascular stiffness and finally 3) Cbfa1 is a critical mediator in differentially induced processes of arterial stiffening. In a more general approach apart from Cbfa1 expression 4) further universal signaling events in arterial stiffness shall be identified.The results of the present project elucidate a novel mechanism that may underlie arterial stiffening (Cbfa1 signaling; hypotheses 1-3) and moreover may identify further potential targets for therapeutic intervention (hypothesis 4).

动脉硬化与年龄增长和多种疾病状态有关，如高血压、充血性心力衰竭、糖尿病或肾功能衰竭。在这里，动脉僵硬可能代表了改变/损害宏观和微循环导致疾病进展的中央病理生理因素。因此，动脉僵硬已被确认为心血管疾病的独立危险因素。因此，动脉僵硬的调节是许多疾病的一个有吸引力的治疗靶点。然而，针对动脉硬化过程中的结构异常和血管信号变化的有效治疗方法目前尚缺乏。血管重构(即动脉硬化的结构相关性)伴随着特定细胞信号通路的基因表达和激活模式的改变。初步数据表明转录因子核心结合因子α1(Cbfa1)作为动脉硬化的媒介起着关键作用。该项目基于Cbfa1是血管纤维化和动脉硬化的通用调节因子的假设。因此，本项目的目的是验证以下假设：1)动脉Cbfa1的表达通常由不同的血管硬化诱因(如机械应激、血管紧张素II或胰岛素、葡萄糖等激素等)诱导，2)Cbfa1活性增加本身导致血管僵硬增加，最后3)Cbfa1在不同诱导的动脉硬化过程中是关键的介质。在更一般的方法中，除了Cbfa1表达4)，还应确定动脉僵硬中的更普遍的信号事件。本项目的结果阐明了可能导致动脉僵硬的新机制(Cbfa1信号；假设1-3)，此外还可能确定更多潜在的治疗干预靶点(假设4)。