The Fat1 Cadherin in Atherosclerotic Vascular Disease

Fat1 钙粘蛋白在动脉粥样硬化性血管疾病中的作用

• 批准号: 8109076
• 负责人: Nicholas E Sibinga
• 金额: $ 41.5万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109076
• 关键词: Ablation; Address; Affect; Arterial Fatty Streak; Arterial Injury; Arteries; Arteriosclerosis; Atherosclerosis; Blood Circulation; Blood Vessels; Blood flow; Boxing; Cadherins; Cause of Death; Cell Culture Techniques; Cell Cycle; Cell Differentiation process; Cell Nucleus; Cell Surface Proteins; Cell physiology; Cell surface; Cells; Cessation of life; Characteristics; Chest Pain; Cleaved cell; Clinical; Coronary Artery Bypass; Development; Differentiation Antigens; Differentiation and Growth; Disease; Environment; Event; Exposure to; Foam Cells; Gene Expression; Genes; Genetic Transcription; Goals; Growth; Growth Factor; Healthcare; Heart Transplantation; Heart failure; Hyperlipidemia; Injury; Kidney; Lead; Ligation; Limb structure; Link; Lipids; Lipoproteins; Maintenance; Mediating; Modeling; Molecular; Molecular Weight; Movement; Mus; Myocardial Infarction; Obstruction; Pathogenesis; Pathway interactions; Phase; Phenotype; Prevention; Process; Proliferating; Proteins; Proteomics; Publishing; Saphenous Vein; Signal Transduction; Site; Smooth Muscle; Smooth Muscle Myocytes; Societies; Stress; Stroke; Structure; Surface; Techniques; Testing; Therapeutic Intervention; Transplantation; Vascular Diseases; Vascular remodeling; Work; Wound Healing; base; cell growth; cell motility; cell type; disability; epigenomics; extracellular; falls; gene function; graft failure; in vivo; mouse model; myocardin; novel; novel strategies; oxidized lipid; promoter; restenosis; vascular smooth muscle cell proliferation

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.

描述（由申请人提供）：血管重塑是临床重要血管疾病发病机制的核心过程，例如动脉粥样硬化、再狭窄、冠状动脉旁路移植失败以及移植心脏和肾脏中发生的动脉硬化。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，可调节血管平滑肌细胞的生长、运动和基因表达，这些是参与血管重塑的关键功能。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增加 Fat1 表达 - 我们假设这有助于维持受压血管壁的生长控制。然而，随着持续暴露于氧化脂质，Fat1 表达水平以及成熟血管平滑肌细胞特征都会下降。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且成熟受损。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 Fat1 片段（Fat1 胞内结构域）。我们发现这个Fat1片段在细胞核中积累，它与其他因子协同激活对于维持成熟血管平滑肌细胞功能很重要的基因。这一观察结果可以解释 Fat1 表达的丧失（如长期脂质暴露所发生的情况）如何与成熟血管平滑肌细胞基因表达和功能的丧失相关。这些发现概述了一种新的分子途径，Fat1 蛋白可以通过该途径将信息从细胞表面的直接环境传递到细胞核，在细胞核中，切割的 Fat1 片段可以指导基因表达并影响细胞活动。该途径的关键点尚未得到充分理解，但可以作为多种血管疾病过程治疗干预的新靶点。该提案的目标是了解 Fat1 表达是如何控制的，定义 Fat1 裂解是如何发生的，并测试 Fat1 表达限制血管重塑和相关动脉粥样硬化疾病的想法。 公共卫生相关性：导致心肌梗塞、中风和血液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。我们的工作涉及新的分子机制，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、血管阻塞和血流受损，并导致心绞痛（胸痛）、心力衰竭、中风、循环受损导致的肢体丧失和死亡等非常常见的疾病。这些细胞培养和相关小鼠模型的研究可能会带来新的预防和治疗方法。