Pro-Inflammatory ECM: Key Roles for Hyaluronan and Versican

促炎 ECM：透明质酸和 Versican 的关键作用

• 批准号: 7140040
• 负责人: Thomas N Wight
• 金额: $ 43.89万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140040
• 关键词: atherosclerosis; atherosclerotic plaque; cell cell interaction; cell type; clinical research; extracellular; extracellular matrix; gene expression; hyaluronate; hyperlipidemia; inflammation; intracellular; laboratory mouse; lead; lipids; macrophage; monocyte; role; smooth muscle; vascular smooth muscle

Specific components of the extracellular matrix (ECM) accumulate in atherosclerosis and promote the inflammatory phase of vascular disease. We have focused on two of these components, hyaluronan and versican, which interact with each other to form higher ordered molecular complexes and not only contribute to ECM expansion during the development of vascular disease but also have a dramatic effect influencing the phenotype of arterial smooth muscle cells. Recently, we found that an ECM enriched in hyaluronan and versican promotes the adhesion of monocytes in a hyaluronan dependent manner suggesting that these specific ECM components may form part of what could be considered a pro-inflammatory ECM. These observations have led us to hypothesize that hyaluronan and versican are produced by vascular cells in response to specific inflammatory stimuli and contribute to the formation of an ECM that binds monocytes. We further hypothesize that monocyte/macrophage also synthesize these ECM components in response to inflammatory stimuli and degrade hyaluronan and versican and that a balance between these two activities partially regulates the phenotype of the monocyte/macrophage. To test this hypothesis, we will have 4 specific Aims. In Aim 1, we will identify the full nature of this specialized ECM and test the requirements for these components for these components in hyaluronan-dependent monocyte adhesion. In Aim 2, we will explore the role that hyperlipidemia and modified lipids play in the generation of this ECM and define the changes in versican and hyaluronan during the development of atherosclerosis. Aim 3 will focus on the synthesis and degradation of versican and hyaluronan by the monocyte/macrophage and the impact of these ECM components monocyte/macrophage proliferation, adhesion and migration. In Aim 4, we will test the importance of this hyaluronan based ECM in the generation of both early and late atherosclerotic lesions by using mouse models of atherosclerosis susceptibility and animals in which specific genes required for the assembly of this ECM have been ablated.

细胞外基质（ECM）的特定成分积聚在动脉粥样硬化中并促进 血管疾病的炎症阶段。我们专注于其中两个组件， 透明质酸和versican，它们相互相互作用以形成较高有序的分子 复合物，不仅有助于在血管疾病发展期间ECM扩张 但也具有影响动脉平滑肌细胞表型的戏剧性效应。最近， 我们发现，富含透明质酸和versican的ECM促进了单核细胞的粘附 透明质酸的依赖性方式表明这些特定的ECM组件可能构成 可以被认为是促炎的ECM。这些观察结果使我们假设 透明质酸和versican是由血管细胞产生的，响应于特定的炎症 刺激并有助于形成结合单核细胞的ECM。我们进一步假设 单核细胞/巨噬细胞还响应炎症而合成了这些ECM成分 刺激和降解透明质酸和versican，这两个活动之间的平衡 部分调节单核细胞/巨噬细胞的表型。为了检验这一假设，我们将 有4个具体目标。在AIM 1中，我们将确定该专业ECM的全部性质，并测试 这些组件对透明质酸依赖性单核细胞中这些组件的要求 粘附。在AIM 2中，我们将探讨高脂血症和改​​良的脂质在 生成此ECM并定义开发过程中Versican和Hyaluronan的变化 动脉粥样硬化。 AIM 3将重点介绍Versican和Hyaluronan的合成和降解 通过单核细胞/巨噬细胞以及这些ECM成分的影响单核细胞/巨噬细胞 增殖，粘附和迁移。在AIM 4中，我们将测试这种透明质酸的重要性 通过使用小鼠模型，ECM生成早期和晚期动脉粥样硬化病变 动脉粥样硬化的敏感性和动物，其中需要特定的基因。 ECM已经消融了。