PROTEIN KINASES AND ENDOTHELIAL CELL ACTIVATION

描述(改编自《调查者摘要》)：内皮细胞 (EC)核因子-kB是参与上调的主要转录因子 大多数促炎基因在EC激活过程中表达，即， 黏附分子、细胞因子/趋化因子和促凝血因子。 这些基因的表达在启动免疫过程中起着关键作用。 循环白细胞靶向微生物作用部位的反应 入侵。不受控制的促炎基因表达可能导致 血管血栓形成和组织坏死，如在 慢性炎症、缺血再灌注损伤、感染性休克和 同种或异种移植排斥反应。一般认为，核因子-kB 转录活性是通过控制转位来调节的 核因子-kB二聚体从胞浆到胞核。一旦进入原子核，它就是 认为核因子-kB二聚体与特定的DNA共有序列结合，其中 它们扮演转录激活剂的角色。首席调查员介绍 有证据表明核移位和DNA结合是 对于核因子-kB转录活性来说是必要的，但不是充分的。在欧共体， 核因子-kB的转录活性受一个额外的 参与MAPK激活、激活核因子-kB二聚体的信号通路 直接或间接。具体地说，调查人员提供证据 RelA的转录活性依赖于它的激活 非典型蛋白激酶ZETA的。和p21ras。此外，他们还 目前的证据表明，cAMP依赖的蛋白激酶(PKA)具有 内皮细胞中核因子-kB活性的双峰调节作用。这就是我们的目的 建议研究已鉴定的激酶模块，进一步鉴定激酶 参与核因子-kB的磷酸化和激活，并鉴定 与RELA发生相互作用时，激活级联的确切水平。 通过解决这些具体目标，首席调查员希望 提供了关于转录调控的新见解 内皮细胞中核因子-kB的活性及其在炎症中的作用。

DESCRIPTION (Adapted from Investigator's Abstract): In endothelial cells (EC) NF-kB is the main transcription factor involved in the upregulation of the majority of pro-inflammatory genes expressed during EC activation, i.e., adhesion molecules, cytokines/chemokines and procoagulant factors. Expression of these genes plays a key role in the initiation of immune responses by targeting circulating leukocytes to sites of microbial invasion. Uncontrolled expression of pro-inflammatory genes can result in vascular thrombosis and tissue necrosis, such as what is observed during chronic inflammation, ischemia-reperfusion injury, septic shock and allograft or xenograft rejection. It is generally assumed that NF-kB transcriptional activity is regulated by controlling the translocation of NF-kB dimers from the cytoplasm to the nucleus. Once in the nucleus, it is believed that NF-kB dimers bind to specific DNA consensus sequences, where they act as transcriptional activators. The principal investigator presents evidence suggesting that nuclear translocation and DNA binding are essential, but not sufficient for, NF-kB transcriptional activity. In EC, the transcriptional activity of NF-kB is tightly regulated by an additional signaling pathway involving the activation of MAPK, activating NF-kB dimers directly or indirectly. Specifically, the investigators provide evidence that the transcriptional activity of RelA is dependent upon the activation of the atypical protein kinase Czeta. and p21ras. Furthermore, they present evidence suggesting that cAMP-dependent Protein Kinase (PKA) has a bimodal function in regulating NF-kB activity in EC. It is the aim of this proposal to study identified kinase modules, further identify the kinases involved in the phosphorylation and activation of NF-kB and to identify the exact level of the kinase cascade at which the interaction with RelA occurs. By addressing these specific aims, the principal investigator hopes to provide new insights concerning the regulation of the transcriptional activity of NF-kB in EC and its contribution to inflammation.