REGULATION OF MONOCYTE FIBRINOLYTIC INHIBITORS

描述：(改编自调查人员摘要)。动脉粥样硬化 心血管疾病仍然是我们社会的主要死亡原因。 动脉粥样硬化病变的发展符合慢性高血压的模型。 对受伤作出反应的炎症。因为它的内部 动脉粥样硬化病变与管腔分离，有 其内血管外炎症微环境。单核细胞是 在这些项目的启动和发展过程中都是必不可少的参与者 损伤，也以纤维蛋白的存在为标志。单核细胞 暴露在炎性刺激下，如脂多糖，会迅速产生高水平的 纤溶酶原激活物抑制物2(PA-2)，一种促进血管生成的分子 抗纤溶微环境，并允许持久性和 纤维蛋白沉积成熟。肿瘤坏死因子(TNF)，还产生 通过刺激单核细胞，可以自分泌的方式诱导这些细胞 在长时间内产生高水平的PAI-2。PAI-2不是 由炎症部位存在的氧化介质灭活，如 可能是PAI-1，PAI-2(但不是PAI-1)是由体内的单核细胞产生的 炎症焦点，因此其产生的变化可能会迅速和 对当前当地形势的变化作出直接反应。PAI-2蛋白 产量与PAI-2mRNA的水平直接相关，PAI-2mRNA是 在一定程度上受控于它们的速率的可诱导变化 退化。在某些情况下，尽管PAI-2似乎在维持 抗纤溶环境对血管外炎性病变影响不大 已知其生产的生理调节。在这 因此，我们建议：(1)确定肿瘤坏死因子在 刺激单核细胞产生PAI-2的持续增加； 确定单核细胞的细胞内信号转导机制 PAI-2对内毒素和肿瘤坏死因子的反应(即 PAI-2的产生可以触发相同的细胞内信号，也可以不同 刺激导致激活不同的细胞内信息，但诱导 同样的反应？)；(3)确定mRNA稳定性的变化是否起到了 在调节单核细胞产生PAI-2方面的重要作用，如果是这样的话 上述细胞内信号通路是否在 确定这种mRNA稳定性的变化。

DESCRIPTION: (Adapted from investigator's abstract). Atherosclerotic cardiovascular disease remains the leading cause of death in our society. The development of atherosclerotic lesions fits the model of chronic inflammation in response to injury. Because the interior of the atherosclerotic lesion is separated from the vessel lumen, there is an extravascular inflammatory microenvironment therein. Monocytes are essential participants in both the initiation and evolution of these lesions, which are also marked by the presence of fibrin. Monocytes exposed to inflammatory stimuli such as LPS rapidly produce high levels of Plasminogen Activator Inhibitor Type 2 (PA-2), a molecule that fosters an antifibrinolytic microenvironment and allows for the persistence and maturation of fibrin deposits. Tumor necrosis factor (TNF), also produced by stimulated monocytes, may, in an autocrine manner, induce these cells to produce high levels of PAI-2 over long periods of time. PAI-2 is not inactivated by the oxidative mediators present at an inflammatory site as would be PAI-1, and PAI-2 (but not PAI-1) is produced by monocytes within the inflammatory focus, so changes in its production can be rapid and in direct response to changes in the immediate local situation. PAI-2 protein production is directly related to levels of PAI-2 mRNA, which are controlled to some extent by inducible changes in their rate of degradation. In some, although PAI-2 seems important in maintaining the anti-fibrinolytic environment of extravascular inflammatory lesions, little is known about the physiological regulation of its production. In this application we therefore propose to: (1) Determine the role of TNF in stimulating a sustained increase in monocyte production of PAI-2; (2) Determine the intracellular signalling mechanisms operative in the monocyte PAI-2 responses to LPS and TNF (i.e., does any stimulus which increases PAI-2 production trigger the same intracellular signals, or can different stimuli cause activation of different intracellular messages and yet induce the same response?); (3) Determine whether changes in mRNA stability play a significant role in regulating monocyte production of PAI-2, and if so whether the above intracellular signalling pathways have a role in determining such changes in mRNA stability.