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FAT cadherins and vascular remodeling

FAT 钙粘蛋白和血管重塑

基本信息

批准号：
10586704
负责人：
Nicholas E Sibinga
金额：
$ 62万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-15 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586704
关键词：
Acceleration Affect Affinity Animal Model Apolipoprotein E Arterial Fatty Streak Arterial Injury Arteries Arteriosclerosis Atherosclerosis Biochemical Biology Blood Vessels Cadherins Cell Differentiation process Cell Nucleus Cell Polarity Cell Proliferation Cell membrane Cell surface Cells Cellular Metabolic Process Cholesterol Complex Cytoplasm Cytoplasmic Protein DNA Development Diabetes Mellitus Disease Disease model Drosophila genus FAT gene Failure Family Fatty acid glycerol esters Feedback GPC3 gene Gene Expression Gene Expression Regulation Genes Genetic Goals Growth Human Hypertension In Vitro Injury Integral Membrane Protein Length Lesion Link Location Mammals Membrane Proteins Metabolic Metabolism Mitochondria Mitochondrial Proteins Modeling Mus Myocardial Infarction Myocardial Ischemia NADH dehydrogenase (ubiquinone)Nuclear Obstruction Oxidative Phosphorylation Pathogenesis Pathway interactions Peptide Hydrolases Peripheral arterial disease Phenotype Positioning Attribute Process Production Proliferating Protein Fragment Protein Isoforms Proteins RNA RNA Splicing Regulation Reporting Role Saphenous Vein Signal Transduction Smoking Smooth Muscle Myocytes Stents Stress Stroke Testing Transplantation Up-Regulation Vascular Diseases Vascular Smooth Muscle Vascular remodeling Vascularization Vein graft cancer cell cell growth cell type comparison control design extracellular gain of function in vivo injured loss of function migration mouse model new therapeutic target programs protein function response restenosis success transcription factor vascular injury

项目摘要

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.

FAT 钙粘蛋白和血管重塑血管重塑是重大血管疾病发病机制中的关键过程。如动脉粥样硬化、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（SMC）活动的因素血管重塑过程中的作用仍不完全清楚。脂肪钙粘蛋白属于一种古老的在后生动物中发现的大型单次 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和极性和跨度对哺乳动物。 FAT1 钙粘蛋白在多种血管疾病动物模型中由 SMC 表达疾病和受伤的人体动脉。我们发现 Fat1 位点失活 SMCs 可以显着增加小鼠模型中的增殖和新内膜形成血管损伤。有趣的是，FAT1 分子经历了复杂的加工：同时裂解 FAT1 胞内结构域 (ICD) 易位至细胞核几年前，我们在线粒体内发现了FAT1片段的积累，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对氧化磷酸化的调节控制，限制呼吸复合物的活性 I和II并抑制细胞生长。 FAT1 对 SMC 基因表达也有显着影响，在体外和体内促进 SMC 标记基因的表达；有趣的是，FAT1ICD 也存在于细胞核中，增加了更直接参与基因的可能性规定。在这个项目中，我们将评估 FAT1 如何从不同位置发出信号细胞，并评估这些活动是否与细胞互补、对立或重叠控制 SMC 表型。我们将研究 FAT1 和 FAT1 中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 的功能进行处理并从而引导至不同的隔室。评估与关键疾病的相关性体内过程，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。