The Fat1 Cadherin in Atherosclerotic Vascular Disease

描述(申请人提供)：血管重塑是临床上重要的血管疾病发病的中心过程，如动脉粥样硬化、再狭窄、冠状动脉旁路移植失败和移植心脏和肾脏的动脉硬化。我们已发表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，它调节血管平滑肌细胞的生长、运动和基因表达，这些都是参与血管重塑的关键功能。脂类对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中的主要结构细胞类型，在动脉粥样硬化斑块发展的早期阶段，Fat1的表达增加-我们假设这有助于维持应激血管壁的生长控制。然而，随着氧化脂质的持续暴露，Fat1的表达水平会随着成熟的血管平滑肌细胞特征的下降而下降。我们对缺乏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蛋白还可以被切割，在细胞内释放一段Fat1(Fat1细胞内结构域)。我们发现这个Fat1片段积聚在细胞核中，在那里它与其他因子合作激活对维持成熟的血管平滑肌细胞功能至关重要的基因。这一观察结果可能解释了脂肪1表达的丧失与成熟血管平滑肌细胞基因表达和功能丧失之间的关系。这些发现勾勒出了一条新的分子途径，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，在那里被切割的Fat1片段可以指导基因表达并影响细胞活动。该通路的关键点尚不清楚，但可作为多种血管疾病过程中治疗干预的新靶点。根据这项建议，我们的目标是了解Fat1的表达是如何控制的，定义Fat1的切割是如何发生的，并测试Fat1的表达对限制血管重塑和相关的动脉粥样硬化性疾病的想法。 公共卫生相关性：导致心肌梗死、中风和循环不良的血管疾病仍然是我们社会死亡、残疾和医疗费用的最大原因。我们的工作致力于解决新的分子机制，这些机制可能控制动脉细胞和动脉壁结构的变化，最终导致动脉粥样硬化、血管阻塞和血液流动障碍，并导致非常常见的疾病，如心绞痛(胸痛)、心力衰竭、中风、由于循环障碍而失去肢体，以及死亡。这些在细胞培养和相关小鼠模型中的研究可能会带来新的预防和治疗方法。

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. PUBLIC HEALTH RELEVANCE: Vascular diseases that cause myocardial infarction, stroke, and poor circulation remain the greatest cause of death, disability, and health care expense in our society. Our work addresses novel molecular mechanisms that may govern the changes in arterial cells and artery wall structure that eventually result in atherosclerosis, vascular obstruction, and impaired blood flow, and lead to such very common diseases as angina (chest pain), heart failure, stroke, limb loss due to impaired circulation, and death. These studies in cell culture and relevant mouse models may lead to new approaches for prevention and treatment.