The Fat1 Cadherin in Atherosclerotic Vascular Disease

描述（申请人提供）：血管重构是临床上重要血管疾病发病的核心过程，如动脉粥样硬化、再狭窄、冠状动脉搭桥失败、移植心脏和肾脏动脉硬化等。我们已发表的和正在进行的研究表明，Fat1是一种非常大的非典型钙粘蛋白细胞表面蛋白，调节血管平滑肌细胞的生长、运动和基因表达，这些关键功能涉及血管重塑。脂质对Fat1表达和功能的影响可能反映了与临床血管疾病的重要联系。血管平滑肌细胞是动脉壁的主要结构细胞类型，在动脉粥样硬化斑块形成的早期阶段增加Fat1的表达-我们假设这有助于维持应激血管壁的生长控制。然而，随着持续暴露于氧化脂质，Fat1表达水平下降，成熟血管平滑肌细胞特征也随之下降。我们对缺乏这种细胞类型的Fat1的小鼠血管损伤的研究表明，在伤口愈合过程中，血管平滑肌细胞过度生长和成熟受损。除了在细胞表面表达外，Fat1蛋白还可以进行裂解，从而在细胞内释放出一个Fat1片段（细胞内结构域）。我们发现这个Fat1片段在细胞核中积累，在那里它与其他因素合作，激活对维持成熟血管平滑肌细胞功能重要的基因。这一观察结果可以解释，随着长时间脂质暴露，Fat1表达的丧失与成熟血管平滑肌细胞基因表达和功能的丧失有关。这些发现概述了一种新的分子途径，通过该途径，Fat1蛋白可以将信息从细胞表面的直接环境传递到细胞核，在细胞核中，被切割的Fat1片段可以指导基因表达并影响细胞活性。该通路的关键点尚不清楚，但可以作为多种血管疾病过程治疗干预的新靶点。我们的目标是了解Fat1表达是如何被控制的，定义Fat1切割是如何发生的，并测试Fat1表达限制血管重塑和相关动脉粥样硬化疾病的观点。

DESCRIPTION (provided by applicant): Vascular remodeling is a central process in the pathogenesis of clinically important vascular diseases such as atherosclerosis, restenosis, coronary artery bypass graft failure, and arteriosclerosis that occurs in transplanted hearts and kidneys. Our published and ongoing studies indicate that Fat1, a very large atypical cadherin cell surface protein, regulates vascular smooth muscle cell growth, movement, and gene expression, key functions involved in vascular remodeling. The effect of lipids on Fat1 expression and function may reflect an important connection to clinical vascular disease. Vascular smooth muscle cells, the major structural cell type in the arterial wall, increase Fat1 expression in early phases of atherosclerotic plaque development - we postulate that this serves to maintain growth control in the stressed vascular wall. With sustained exposure to oxidized lipids, however, Fat1 expression levels fall, along with mature vascular smooth muscle cell characteristics. Our studies of vascular injury in mice lacking Fat1 specifically in this cell type show excessive growth and impaired maturation of vascular smooth muscle cells during wound healing. In addition to its expression on the cell surface, the Fat1 protein can undergo cleavage, which releases a fragment of Fat1 (the Fat1 intracellular domain) within the cell. We have found that this Fat1 fragment accumulates in the cell nucleus, where it co-operates with other factors to activate genes important for maintenance of mature vascular smooth muscle cell functions. This observation may explain how loss of Fat1 expression, as occurs with prolonged lipid exposure, is linked to the loss of mature vascular smooth muscle cell gene expression and function. These findings outline a new molecular pathway by which the Fat1 protein can relay information from the immediate environment at the surface of a cell to the cell nucleus, where the cleaved Fat1 fragment can direct gene expression and affect cellular activity. Critical points of this pathway are not yet well understood, but could serve as novel targets for therapeutic intervention in multiple vascular disease processes. Our goals under this proposal are to understand how Fat1 expression is controlled, define how Fat1 cleavage occurs, and to test the idea that Fat1 expression acts to limit vascular remodeling and associated atherosclerotic disease.