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）的特定成分在动脉粥样硬化中积聚并促进 血管疾病的炎症阶段。我们重点关注其中两个组件， 透明质酸和多功能蛋白聚糖，它们相互作用形成更有序的分子 复合物不仅有助于血管疾病发展过程中 ECM 的扩张 而且对动脉平滑肌细胞的表型也有显着影响。最近， 我们发现富含透明质酸和多功能蛋白聚糖的 ECM 可促进单核细胞的粘附 透明质酸依赖性方式表明这些特定的 ECM 成分可能构成 什么可以被认为是促炎 ECM。这些观察使我们推测 透明质酸和多功能蛋白聚糖是由血管细胞响应特定炎症而产生的 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/巨噬细胞也合成这些 ECM 成分以应对炎症 刺激并降解透明质酸和多功能蛋白聚糖，并且这两种活性之间的平衡 部分调节单核细胞/巨噬细胞的表型。为了检验这个假设，我们将 有 4 个具体目标。在目标 1 中，我们将确定这种专用 ECM 的全部性质并测试 乙酰透明质酸依赖性单核细胞对这些成分的需求 附着力。在目标 2 中，我们将探讨高脂血症和修饰脂质在 该 ECM 的生成并定义开发过程中多功能蛋白聚糖和透明质酸的变化 动脉粥样硬化。目标3将重点关注多功能蛋白聚糖和透明质酸的合成和降解 受单核细胞/巨噬细胞以及这些 ECM 成分单核细胞/巨噬细胞的影响 增殖、粘附和迁移。在目标 4 中，我们将测试这种基于透明质酸的重要性 使用小鼠模型进行 ECM 在早期和晚期动脉粥样硬化病变产生中的作用 动脉粥样硬化易感性以及组装该动脉粥样硬化所需的特定基因的动物 ECM已被消融。