Endothelial Biology

这个项目将进一步发展镰状病作为再灌注损伤生理学的一个例子 重点研究肺静脉组织因子异常表达的内皮激活终点 恩多塞。这种关注是合理的，因为：[a]它将扩展对TF生物学的理解;[B]它 包括内皮细胞活化的稳健终点指标;并且[c]其具有很大的潜在重要性 镰状病，其中受影响的个体具有凝血病和血栓形成。我们将研究5 具体目标。[1]确定镰状小鼠的不同之处，这导致它们-而不是正常小鼠- 发展内皮TF表达。我们的主要假设是炎症起主要作用， 这是由外周血单核细胞介导的，并由来自内皮eNOS的NO调节。 [2]删除。[3]评估内皮TF表达的位置、功能和相关性。我们的关键 假设：内皮TF是功能性的，在内皮细胞的腔侧表达; 并且TF表达的抑制（在小鼠和人中）将通过凝血的减少而被消除 激活状态[4]在分子和整体小鼠水平上确定内皮TF的潜在机制 表达和抑制。我们的主要假设是，虽然NF κ B对内皮TF是允许的， 在镰状小鼠模型中表达，Egr-1是必需的。[5]研究为什么在血管内皮细胞中存在内皮异质性， TF表达。内皮TF表达局限于肺，在该器官内局限于静脉， 只有一些静脉。理解这个非常有趣的内皮细胞表型的例子的原因 异质性不仅具有普遍的生物学意义，而且具有一定的医学重要性。给你钥匙 假设TF阳性静脉表现出这种表型，是因为之前的低氧应激大于 TF阴性静脉我们将研究镰状细胞小鼠，以确定它们为什么异常 易缺氧并表达组织因子，触发血液凝固。这些的重要性 这些研究很好地帮助我们开发了一种新的治疗镰状病的方法， 影响孩子的问题。

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.