REGULATION OF MONOCYTE FIBRINOLYTIC INHIBITORS

描述：（改编自研究者摘要）。 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 炎症是对损伤的反应。 因为内部的 当动脉粥样硬化病变与血管腔分离时， 微环境中的炎症反应。 单核细胞 在这两个启动和发展的重要参与者， 病变，其也以纤维蛋白的存在为标志。 单核细胞 暴露于炎症刺激（例如LPS）后迅速产生高水平的 纤溶酶原激活物抑制剂2型（PA-2），一种促进纤溶酶原激活物抑制剂2型（PA-2）的分子， 抗纤溶微环境，并允许持久性和 纤维蛋白沉积物的成熟。 肿瘤坏死因子（TNF），也产生 通过刺激单核细胞，可以以自分泌的方式诱导这些细胞 长时间产生高水平的派-2。 派-2不是 被存在于炎症部位的氧化介质灭活， 可能是派-1，派-2（而不是派-1）由单核细胞产生， 炎症病灶，因此其产生的变化可能很快， 直接应对当地形势的变化。 派-2蛋白 派-2 mRNA的水平直接相关， 在一定程度上受其生长速率的诱导性变化的控制， 降解 在某些情况下，尽管派-2似乎在维持 血管外炎性病变的抗纤溶环境，很少 已知其产生的生理调节。 在这 因此，我们建议：（1）确定TNF在 刺激派-2的单核细胞产生的持续增加;（2） 确定单核细胞中的细胞内信号传导机制 派-2对LPS和TNF的反应（即，任何刺激， 派-2的产生触发相同的细胞内信号，或者可以不同 刺激引起不同细胞内信息的激活， 同样的答案？）; (3)确定mRNA稳定性的变化是否发挥作用 在调节单核细胞产生派-2中的重要作用，如果是这样， 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.