ROLE OF OSTEOPONTIN IN GRANULOMATOUS INFLAMMATION

肉芽肿形成背后的关键调控事件，特别是肉芽肿基质的作用还不清楚。 我们最近证实了早期T细胞活化基因Eta-1（也称为骨桥蛋白{OPN}，一种骨基质酸性糖蛋白）在结核结节病的活动性肉芽肿病变中的存在。 我们的初步数据表明，Eta-1/OPN是一种有效的化学引诱剂，粘附素和增殖的共刺激T淋巴细胞在体外。 这些数据、小鼠骨桥蛋白减少与宿主对细胞内病原体（如体内恙虫病立克次体）的反应缺陷的相关性以及骨桥蛋白是单核细胞和巨噬细胞的有效化学引诱物的事实表明，Eta-1/OPN代表一类新的含RGD的细胞因子，其调节T细胞和巨噬细胞功能，在（肺）肉芽肿性炎症的启动和维持中起关键作用。具体而言，我们假设巨噬细胞、淋巴细胞、内皮细胞和上皮细胞表达Eta-1/OPN是肉芽肿形成的早期重要事件，其调节炎性细胞运输、细胞活化和细胞因子产生、增殖和细胞死亡。 该基金拟阐明其免疫功能并研究其在肉芽肿形成中的作用。体外研究包括表征免疫细胞和肺细胞产生的Eta-1/OPN以及这些细胞产生的磷酸化和糖基化变体。 将研究纯化的和重组的OPN对T细胞功能的影响。将进行体内研究以确定Eta-1/OPN在肺部肉芽肿形成中的作用。 将使用一种模型，其中通过含有抗原的琼脂糖凝胶珠的栓塞诱导肉芽肿，所述抗原诱导依赖于Th 1和Th 2细胞因子的肉芽肿形成。 该模型将应用于遗传工程改造的Eta-1/OPN缺陷型小鼠和野生型对照。

The key regulatory events behind granuloma formation and particularly the role of the granuloma matrix are not well understood. We have recently demonstrated the presence of the early T-cell activation gene Eta-1 (also known as osteopontin {OPN}, a bone matrix acidic glycoprotein) in active granulomatous lesions of tuberculosis rid sarcoidosis. Our preliminary data demonstrate that Eta-1/OPN is a potent chemoattractant, adhesin and proliferative co-stimulant for T lymphocytes in vitro. These data, the association of reduced osteopontin in mice with defective host response to intracellular pathogens such as Rickettsia tsutsugamushi in vivo, and the fact that steopontin is a potent chemoattractant for monocytes and macrophages suggest that Eta-1/OPN represents a new class of RGD-containing cytokine which regulates T cell and macrophage function, serving a key role in the initiation and maintenance of (lung) granulomatous inflammation. Specifically, we hypothesize that the expression of Eta-1/OPN by macrophages, lymphocytes, endothelial and epithelial cells is an early and important event in granuloma formation which regulates inflammatory cell traffic, cellular activation and cytokine production, proliferation, and cell death. This grant proposes to elucidate its immunologic functions and study its role in granuloma formation. In vitro studies include characterizing the production of Eta-1/OPN by immune cells and lung cells and the phosphorylation and glycosylation variants produced by these cells. The effects on T cell function of purified and recombinant OPN will be studied. In vivo studies will be performed to determine the role of Eta-1/OPN in the formation of granulomas in he lung. A model will be used in which granulomas are induced by the embolization of sepharose beads containing antigens which induce the formation of granulomas dependent on Th1 and Th2 cytokines. The model will be applied to a genetically engineered Eta-1/OPN deficient mouse and wild type controls.