FAT cadherins and vascular remodeling

脂肪钙粘附素与血管重塑 血管重塑是血管重塑等重大血管疾病发病的关键过程。 动脉粥样硬化、再狭窄、大隐静脉移植物闭塞和移植相关 动脉硬化。控制血管平滑肌细胞(SMCs)活性的因素 在血管重塑过程中，人们仍然不完全了解。脂肪钙粘附素属于一种古老的 广泛存在于后生动物体内的大的、单通道的I型跨膜蛋白家族； 这些蛋白质的保守功能影响果蝇细胞的生长、极性和跨度 对哺乳动物来说。FAT1钙粘附素在多种血管病变动物模型中的表达 疾病和受伤的人体动脉中。我们发现Fat1基因座的失活 SMC可显著增加血管内皮细胞的增殖和新生内膜形成 血管损伤。有趣的是，FAT1分子经历了复杂的处理：当切割时 并报道了FAT1胞内域(ICD)到细胞核的移位 几年前，我们发现线粒体中积累了FAT1片段，其中 这些FAT1mito物种选择性地与内膜蛋白相互作用，并发挥关键作用 氧化磷酸化的调控，限制呼吸复合体的活性 I和II，并抑制细胞生长。FAT1对SMC基因表达也有实质性影响， 促进SMC标记基因在体外和体内的表达；有趣的是，FAT1ICD 也在细胞核中发现，这增加了更直接参与基因的可能性 监管。在这个项目中，我们将评估FAT1如何从内部不同位置发出信号 并评估这些活动是互补的、对立的还是重叠的 对照SMC表型。我们将研究FAT1和FAT1的细胞内和细胞外序列 与结构相关蛋白FAT4和DCHS1的相互作用可能控制FAT1的方式 经过处理，并因此被引导到不同的隔间。评估与关键疾病的相关性 过程中，我们将评估这些信号活动如何影响血管重塑和 小鼠模型中的动脉粥样硬化。

FAT cadherins and vascular remodeling Vascular remodeling is a critical process in the pathogenesis of major vascular diseases such as atherosclerosis, restenosis, saphenous vein graft occlusion, and transplant-associated arteriosclerosis. Factors that control the activities of vascular smooth muscle cells (SMCs) during vascular remodeling remain incompletely understood. Fat cadherins belong to an ancient family of large, single pass type I transmembrane proteins found throughout Metazoans; conserved functions of these proteins affect cell growth and polarity and span from Drosophila to mammals. The FAT1 cadherin is expressed by SMCs in multiple animal models of vascular disease and in injured human arteries. We have found that inactivation of the Fat1 locus in SMCs permits dramatic increases in proliferation and neointimal formation in a mouse model of vascular injury. Interestingly, the FAT1 molecule undergoes complex processing: while cleavage and translocation of the FAT1 intracellular domain (ICD) to the cell nucleus was reported several years ago, we found an accumulation of FAT1 fragments within mitochondria, wherein these FAT1mito species interact selectively with inner membrane proteins and exert critical regulatory control over oxidative phosphorylation, limiting the activities of respiratory Complexes I and II and inhibiting cell growth. FAT1 also has substantial effects on SMC gene expression, promoting expression of SMC marker genes both in vitro and in vivo; interestingly, the FAT1ICD is also found in the cell nucleus, raising the possibility of more direct involvement in gene regulation. In this project, we will assess how FAT1 signals from different locations within the cell, and assess whether these activities are complementary, oppositional, or overlapping to control SMC phenotype. We will investigate intra- and extracellular sequences in FAT1 and interactions with structurally-related proteins FAT4 and DCHS1 that may control how FAT1 is processed and thereby directed to distinct compartments. To assess relevance to key disease processes in vivo, we will assess how these signaling activities affect vascular remodeling and atherosclerosis in mouse models.