Osteopontin Proteolysis and Inflammation

骨桥蛋白水解与炎症

• 批准号: 7140035
• 负责人: Cecilia M Giachelli
• 金额: $ 25.67万
• 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/7140035
• 关键词: atherosclerosis; atherosclerotic plaque; bone marrow transplantation; cell cell interaction; cell surface receptors; cell type; extracellular; gene expression; inflammation; intracellular; laboratory mouse; lead; lipids; macrophage; osteopontin; proteolysis; smooth muscle; thrombin

Osteopontin (OPN) is a multifunctional, secreted phosphoprotein with beneficial anticalcific effects on pathological calcification. Recent data suggest that OPN may also play a critical role in development of various chronic inflammatory diseases, including atherosclerosis. Furthermore, growing evidence indicates that multiple, proteolytically processed forms of OPN are generated under inflammatory conditions. However, virtually nothing is known about the specific form(s) and function(s) of OPN important in these settings. We propose that a common feature of chronic inflammatory conditions is a requirement for OPN function in macrophages. Specifically, we hypothesize that 1) OPN mediates macrophage recruitment, activation, and survival in atherosclerotic plaques, 2) thrombin, as well as matrix metalloproteases secreted by inflammatory cells modify OPN activity, and 3) that specific OPN proteolytic fragments are required for plaque progression in vivo. Three Specific Aims are proposed to address these hypotheses. In Specific Aim 1, the role of macrophage- and lymphocyte-derived OPN in atherosclerotic lesion initiation and progression in chow-fed ApoE-/- mice will be determined using bone marrow transplant studies. In Specific Aim 2, the role of OPN and its receptors in the modulation of macrophage functions in vitro, including adhesion, migration, survival and activation, will be examined. Finally, in Specific Aim 3, the role of two integrin binding domains, RGD and SLAYGLR domains, of OPN as well as MMPderived OPN proteolytic fragments will be determined during atherosclerotic lesion development and progression in ApoE-/- mice using bone marrow over-expressing these OPN fragments on a macrophage specific promoter. Understanding differences in the mechanisms and structure/function relationships governing inflammatory properties of OPN could help create specific therapeutics targeting these distinct functions.

骨桥蛋白(OPN)是一种多功能的分泌型磷蛋白，具有良好的抗钙化作用。 关于病理性钙化。最近的数据表明，OPN也可能在 各种慢性炎症性疾病的发展，包括动脉粥样硬化。此外， 越来越多的证据表明，产生了多种蛋白质分解处理的OPN形式 在炎症条件下。然而，对具体的形式几乎一无所知(S)和 OPN的功能(S)在这些设置中很重要。我们认为慢性病的一个共同特征是 炎症条件是巨噬细胞骨桥蛋白功能的必要条件。具体来说，我们 假设1)OPN介导巨噬细胞的募集、激活和存活 动脉粥样硬化斑块，2)凝血酶，以及炎症分泌的基质金属蛋白酶 细胞改变OPN的活性，以及3)斑块需要特定的OPN蛋白水解物片段 在体内的进展。为了解决这些假设，本文提出了三个具体目标。具体而言 目的1、巨噬细胞和淋巴细胞来源的骨桥蛋白在动脉粥样硬化病变的发生和发展中的作用。 饮食喂养的载脂蛋白E-/-小鼠的进展将通过骨髓移植研究来确定。在……里面 特异靶2，骨桥蛋白及其受体在体外巨噬细胞功能调节中的作用 包括黏附、迁移、存活和激活。最后，在具体目标3中， OPN和MMP两个整合素结合域RGD和SLAYGLR结构域的作用 OPN蛋白分解片段将在动脉粥样硬化病变发展过程中被确定 在ApoE-/-小鼠中使用骨髓过度表达这些OPN片段的研究进展 巨噬细胞特异性启动子。了解不同的机制和 控制OPN炎症特性的结构/功能关系可以帮助创建特定的 针对这些不同功能的治疗。