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 导致不稳定冠状动脉病变的形成， 破裂和随后的血栓形成。细胞粘附分子 参与炎症细胞的募集，在细胞-细胞和 细胞-基质相互作用，并在信号转导内的发展 动脉粥样硬化病变CD 44是一种广泛表达的CAM， 透明质酸（一种细胞外基质糖胺聚糖）的主要受体 聚集在动脉粥样硬化病变处。CD 44以低亲和力表达， 在大多数原代细胞上处于高亲和力状态，但在 存在炎症刺激。CD 44参与了多种 慢性炎症反应。我们研究了CD 44在肿瘤细胞中的作用。 apoE缺陷小鼠动脉粥样硬化的发展。CD 44缺乏没有 对血浆胆固醇水平的影响，但动脉粥样硬化的程度， 与apoE 4-.CD44+I相比，apoE-/-.C0444-/-小鼠显著降低。 同窝出生的拟议研究的目标是确定分子和 CD 44促进动脉粥样硬化形成的细胞机制。以下是 具体目标：1.明确CD 44在促进动脉粥样硬化中的作用。的 CD 44在动脉粥样硬化病变不同发展阶段的作用将 在不同年龄的apoE-/-.CD44-/-小鼠中测定，并通过用 抗CD 44抗体。CD 44缺乏对老年人动脉粥样硬化的影响 将测定LDLRI-小鼠。我们将评估CD 44的功能激活， 并确定参与促进动脉粥样硬化形成的CD 44的分子形式。 2.确定CD 44表达对骨髓源性 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CD 44在动脉粥样硬化形成中的作用。我们将确定CD 44在造血细胞上 细胞或骨髓嵌合体中的非造血细胞 促进动脉粥样硬化形成。在内皮细胞上表达CD 44的转基因小鼠 而血管平滑肌细胞在CD 44缺乏的背景下， 并分析了动脉粥样硬化。可溶性CD 44对 将确定动脉粥样硬化形成。3.确定细胞和分子 CD 44/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）CD 44/HA相互作用促进白细胞归巢至位点 B）CD 44和HA介导巨噬细胞-平滑肌细胞 细胞相互作用; c）CD 44用于组织富含透明质酸的细胞周 基质;和d）CD 44缺乏对血管基因表达谱的影响 使用微阵列技术。由于CD 44在炎症中起着重要作用， 但不是正常白细胞循环所必需的， 作为新型治疗干预的潜在靶点， 动脉粥样硬化

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.