Proinflammatory Effects of CD44 on Atherosclerosis

描述(申请人摘要)：动脉粥样硬化是一种炎症过程 这会导致形成不稳定的冠状动脉病变，容易 破裂和随后的血栓形成。细胞黏附分子(CAM) 参与炎症细胞的募集，在细胞内和细胞内 细胞-基质相互作用，以及在发育过程中的信号转导 动脉粥样硬化病变。CD44是一种广泛表达的CAM，作为一种 透明质酸的主要受体，一种细胞外基质糖胺聚糖 积聚在动脉粥样硬化性病变中。CD44以低亲和力表达 状态，但被激活为高亲和力状态的 炎性刺激的存在。CD44与多种疾病有关 慢性炎症反应。我们研究了CD44在细胞周期中的作用。 载脂蛋白E缺陷小鼠动脉粥样硬化的发生。CD44缺乏症没有 对血浆胆固醇水平的影响，但动脉粥样硬化的程度 与apoE4-.CD44+I相比，apoE-/-.C0444-/-小鼠显著减少。 一窝产仔。拟议研究的目标是确定分子和 CD44促进动脉粥样硬化形成的细胞机制。以下是以下内容： 具体目的：1.明确CD44在促进动脉粥样硬化中的作用。这个 CD44在动脉粥样硬化病变不同发展阶段的作用 在不同年龄的apoE-/-.CD44-/-小鼠中测定，并通过治疗 抗CD44抗体。CD44缺乏对老年人动脉粥样硬化的影响 LDLRI-小鼠将被检测。我们将评估CD44的功能激活 并确定CD44参与促进动脉粥样硬化形成的分子形式。 2.测定CD44表达对骨髓来源的相对影响 造血细胞与血管细胞在动脉粥样硬化形成中的作用 可溶性CD44在动脉粥样硬化形成中的作用。我们将确定CD44在造血细胞上的作用 骨髓嵌合体中单独或单独非造血细胞上的细胞 促进动脉粥样硬化的形成。在内皮细胞上表达CD44的转基因小鼠 而血管平滑肌细胞对CD44缺乏的背景会 创建并分析了动脉粥样硬化。可溶性CD44在血管紧张素转换酶中的作用 动脉粥样硬化的形成将被确定。3.确定细胞和分子 CD44/HA相互作用促进动脉粥样硬化形成的机制。我们将测试 假设：a)CD44/HA相互作用促进白细胞归巢 B)CD44和HA介导巨噬细胞-平滑肌 细胞相互作用；c)CD44作用于组织富含透明质酸的细胞周围 D)CD44缺乏对血管基因表达谱的影响 使用微阵列技术。由于CD44在炎症中起着重要作用 但不是正常的白细胞循环所必需的，尤其是 作为新的治疗干预措施的潜在靶点具有吸引力 动脉硬化。

DESCRIPTION (Applicant's abstract): Atherosclerosis is an inflammatory process that results in the formation of unstable coronary lesions vulnerable to disruption and subsequent thrombosis. Cell adhesion molecules (CAMs) participate in the recruitment of inflammatory cells, in cell-cell and cell-matrix interactions, and in signal transduction within the developing atherosclerotic lesion. CD44 is a widely expressed CAM that serves as a principal receptor for hyaluronan, an extracellular matrix glycosaminoglycan that accumulates in atheroslerotic lesions. CD44 is expressed in a low affinity state on most primary cells but is activated to a high affinity state in the presence of inflammatory stimuli. CD44 has been implicated in a variety of chronic inflammatory responses. We investigated the role of CD44 in the development of atherosclerosis in apoE-deficient mice. CD44-deficiency had no effect on plasma cholesterol levels but the extent of atherosclerosis in apoE-/-.C0444-/- mice was markedly reduced compared to apoE4-.CD44+I. littermates. The goal of the proposed studies is to determine the molecular and cellular mechanisms by which CD44 promotes atherogenesis. The following are the specific aims: 1. Define the role of CD44 in promoting atherosclerosis. The role of CD44 at different stages of development of atherosclerotic lesions will be determined in apoE-/-.CD44-/- mice of different ages and by treatment with anti-CD44 antibodies. The impact of CD44 deficiency on atherosclerosis in LDLRI- mice will be determined. We will assess functional activation of CD44 and determine the molecular form of CD44 involved in promoting atherogenesis. 2. Determine the relative effects of CD44 expression on bone marrow-derived hematopoietic cells versus vascular cells on atherogenesis and define the role of soluble CD44 in atherogenesis. We will determine if CD44 on hematopoietic cells alone or on non-hematopoietic cells alone in bone marrow chimeras promotes atherogenesis. Transgenic mice expressing CD44 on endothelial cells and vascular smooth muscle cells on the background of CD44 deficiency will be created and atherosclerosis analyzed. The contribution of soluble CD44 to atherogenesis will be determined. 3. Determine the cellular and molecular mechanisms by which CD44/HA interactions promote atherogenesis. We will test the hypotheses that: a)CD44/HA interactions promote leukocyte homing to sites of atherosclerotic lesions; b) CD44 and HA mediate macrophage-smooth muscle cell interactions; c) CD44 acts to organize hyaluronan-rich pericellular matrix; and d) CD44 deficiency impacts on the vascular gene expression profile using microarray technology. Since CD44 plays an important role in inflammation but is not required for normal leukocyte circulation, it is particularly attractive as a potential target for novel therapeutic interventions in atherosclerosis.