Endothelial Biology

该项目将进一步发展镰刀病作为再灌注损伤生理学的例子 并着重探讨肺静脉组织因子异常表达的内皮激活终点 内皮细胞。这种关注是合理的，因为：[a]它将扩大对转铁蛋白生物学的理解；[b]它 包括一个强大的内皮细胞激活终点指标；[c]它具有很大的潜在重要性 N镰刀病，受影响的人有凝血障碍和血栓。我们将检查5个 明确的目标。[1]找出镰刀鼠的不同之处，这会导致它们--而不是正常鼠-- 发展内皮细胞因子的表达。我们的关键假设是炎症起主要作用，而且 这是由外周血单核细胞介导的，并受到内皮eNOS的NO的调节。 [2]已删除。[3]评估内皮组织因子表达的位置、功能和相关性。我们的钥匙 假说是：内皮组织因子具有功能，并且在内皮细胞的管腔侧表达； 而抑制TF的表达(在小鼠和人类中)将与凝血功能的减少平行 激活状态。[4]在分子和整个小鼠水平上确定内皮细胞转铁蛋白的机制 表达和抑制。我们的关键假设是，虽然NFKB对内皮因子是允许的 在镰刀鼠模型中，Egr-1的表达是必不可少的。[5]检查为什么存在内皮细胞异质性 Tf表达式。内皮组织因子的表达仅限于肺，并在该器官内至静脉，以及 只有一些静脉。理解这个非常有趣的内皮细胞表型例子的原因 异质性不仅具有普遍的生物学意义，而且具有一定的医学意义。给你，我们的钥匙 假设Tf阳性的静脉表现出这种表型，是因为先前的低氧应激比 Tf阴性静脉。版面总结：我们将研究镰状细胞小鼠以确定它们异常的原因 易缺氧并表达组织因子，触发血液凝结。这些因素的重要性 研究表明，它们很好地帮助我们开发了一种预防大中风的镰刀病的新疗法。 受影响儿童的问题。

This Project will further develop the theme of sickle disease as an example of reperfusion injury physiology and focus on the endothelial activation endpoint of abnormal expression of tissue factor by pulmonary vein ndothelium. This focus is justified because: [a] it will extend the understanding of TF biology; [b] it comprises a robust endpoint indicator of endothelial cell activation; and [c] it is of great potential importance n sickle disease, in which affected individuals have a coagulopathy and thromboses. We will examine 5 Specific Aims. [1] Identify what is different about sickle mice, that leads them - but not normal mice - to develop endothelial TF expression. Our Key Hypotheses are that inflammation plays the primary role, and that this is mediated by peripheral blood monocytes, and modulated by NO from endothelial eNOS. [2]deleted. [3] Assess the location, functionality, and relevance of endothelial TF expression. Our Key Hypotheses are: that endothelial TF is functional and expressed on the lumen side of the endothelial cell; and that inhibition of TF expression (in mouse and human) will be paralleled by diminution in coagulation activation state. [4] Identify, at molecular and whole mouse levels, the mechanism underlying endothelial TF expression and inhibition. Our Key Hypotheses is that while NFKB is permissive for endothelial TF expression in sickle mouse model, Egr-1 is essential. [5] Examine why there is endothelial heterogeneity in TF expression. Endothelial TF expression is confined to the lungs, and within this organ to the veins, and only some veins. Understanding the reason for this very interesting example of endothelial phenotype heterogeneity is not only of general biological interest, but also of some medical importance. Here, our Key Hypotheses is that the TF positive veins exhibit this phenotype because of greater prior hypoxic stress than the TF negative veins. LAY SUMMARY: We will study sickle cell mice to determine why they are abnormally susceptible to hypoxia and express tissue factor, the trigger of blood clotting. The importance of these studies is that they well help us develop a novel therapy for sickle disease that will prevent the large stroke problem in affected kids.