ENDOTHELIAL CELL RESPONSES TO SHOCK AND TRAUMA

缺血性(缺氧性)细胞损伤是各种组织损伤的基础 临床疾病。越来越多的证据表明， 组织损伤发生在缺血组织的复氧(再灌注)之后。 缺血后的细胞死亡可能与固有细胞的激活有关 [自杀]程序导致细胞凋亡。可能导致再灌注损伤 由信号触发的炎症级联反应的激活 因缺血或再灌流而产生，导致细胞凋亡。 了解细胞活化/凋亡的分子基础 缺氧/复氧损伤可能提示新的治疗方法 与之相关的重大临床疾病。申请人假定 有几个信号通路参与内皮细胞。 S对缺氧/复氧的反应。申请人假设 应激激活蛋白激酶和p38激酶(SAPK/p38)通路 参与了促炎反应的激活，并且，沿着 与P53蛋白共同促进细胞凋亡。相反，核因子-kB途径是 是诱导细胞保护通路所必需的 既有促凋亡作用，也有促炎作用。申请人建议 SAPK/p38通路或P53蛋白可能是一个有吸引力的靶点 低氧/复氧诱导的损伤，其中抑制核因子-kB 单独的信号通路可能通过以下方式影响内皮细胞的存活 防止细胞保护蛋白的诱导。总目标 这一应用的目的是阐明促进 存活率和那些激活促炎或促凋亡的细胞 内皮细胞在缺氧/复氧过程中的反应。这个 这项建议的具体目的是：1.确定表达 和调控内皮细胞中的细胞保护蛋白 低氧/复氧；2.确定核因子-kB在血管内皮细胞损伤中的作用。 内皮细胞中促炎基因和细胞保护基因的诱导 细胞在缺氧/复氧中的作用；3.确定SAPK/p35的作用 促炎症和促凋亡反应中的激酶途径 内皮细胞缺氧/复氧；4.测定血管内皮细胞 血管内皮细胞白介素8基因表达的调控机制 细胞在缺氧/复氧过程中的作用；以及5.确定 P53蛋白在缺氧诱导内皮细胞凋亡中的作用

Ischemic (hypoxic) cell injury underlies tissue damage in diverse clinical disorders. Increasing evidence indicates that additional tissue damage follows reoxygenation (reperfusion) of ischemic tissue. Cell death following ischemia may involve activation of a intrinsic cell [suicide] program leading to apoptosis. Reperfusion injury may result from activation of an inflammatory cascade, triggered by signals generated by ischemia or following reperfusion, leading to apoptosis. Understanding the molecular basis of cellular activation/apoptosis in hypoxia/reoxygenation injury may suggest new approaches to therapy of the associated major clinical disorders. The applicant postulates that there are several signaling pathways involved in the endothelial cell s response to hypoxia/reoxygenation. The applicant hypothesizes that the stress-activated protein kinase and p38 kinase (SAPK/p38) pathways are involved in the activation of pro-inflammatory responses, and, along with p53 protein promote apoptosis. In contrast, the NF-kB pathway is required for the induction of cytoprotective pathways that is anti- apoptotic as well as pro-inflammatory. The applicant suggests that the SAPK/p38 pathways or the p53 protein may be an attractive target for hypoxia/reoxygenation induced injury, where as inhibition of the NF-kB signaling pathway alone may compromise endothelial cell survival by preventing the induction of cytoprotective proteins. The overall goal of this application is to elucidate the pathways and genes that promote survival and those that activate pro-inflammatory or pro-apoptotic responses in endothelial cells during hypoxia/reoxygenation. The specific aims in this proposal are thus: 1. to determine the expression and regulation of cytoprotective proteins in endothelial cells during hypoxia/reoxygenation; 2. to determine the role of NF-kB in the induction of pro-inflammatory and cytoprotective genes in endothelial cells during hypoxia/reoxygenation; 3. to define the role of SAPK/p35 kinase pathways in pro-inflammatory and pro-apoptotic responses to endothelial cells in hypoxia/reoxygenation; 4. to determine the mechanisms that regulate interleukin-8 gene expression in endothelial cells during hypoxia/reoxygenation; and 5. to determine the role of the p53 protein in hypoxia induced endothelial cell apoptosis.