FAT cadherins and vascular remodeling

FAT 钙粘蛋白和血管重塑

• 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
• 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

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.

脂肪钙粘蛋白与血管重构 血管重塑是主要血管疾病发病机制中的关键过程， 如动脉粥样硬化、再狭窄、隐静脉移植物闭塞和移植相关的 动脉硬化控制血管平滑肌细胞（SMC）活动的因素 在血管重塑中的作用仍然不完全清楚。脂肪钙粘蛋白属于一种古老的 在后生动物中发现的一个大的、单次通过的I型跨膜蛋白家族; 这些蛋白质的保守功能影响细胞生长和极性，并从果蝇跨度 哺乳动物。FAT 1钙粘蛋白在多种血管性心脏病动物模型中由SMC表达 疾病和受伤的人体动脉。我们已经发现，Fat 1基因座的失活， 平滑肌细胞允许增殖和新生内膜形成的小鼠模型中的显着增加， 血管损伤有趣的是，FAT 1分子经历了复杂的加工过程： 报道了FAT 1胞内结构域（ICD）向细胞核的易位 几年前，我们发现线粒体内积累了FAT 1片段，其中 这些FAT 1 mito种类选择性地与内膜蛋白相互作用， 调节氧化磷酸化，限制呼吸复合物的活动 抑制细胞生长。FAT 1对SMC基因表达也有显著影响， 促进SMC标记基因在体外和体内的表达;有趣的是，FAT 1 ICD 在细胞核中也发现了，这增加了更直接参与基因表达的可能性。 调控在这个项目中，我们将评估FAT 1信号如何从不同的位置内， 细胞，并评估这些活动是否是互补的，对立的，或重叠， 对照SMC表型。我们将研究FAT 1的细胞内和细胞外序列， 与结构相关的蛋白质FAT 4和DCHS 1的相互作用，可能控制FAT 1如何 处理并由此引导至不同的隔室。评估与关键疾病的相关性 在体内过程中，我们将评估这些信号活动如何影响血管重塑， 动脉粥样硬化小鼠模型。