PROTEIN KINASES AND ENDOTHELIAL CELL ACTIVATION

描述（改编自研究者摘要）：内皮细胞 (EC)NF-kB是参与转录因子表达上调的主要转录因子。 大多数促炎基因在EC活化期间表达，即， 粘附分子、细胞因子/趋化因子和促凝血因子。 这些基因的表达在免疫启动过程中起着关键作用。 通过将循环白细胞靶向微生物 入侵 促炎基因的不受控制的表达可导致 血管血栓形成和组织坏死，例如在 慢性炎症、缺血-再灌注损伤、败血性休克和 同种异体移植物或异种移植物排斥。 通常假设NF-kB 转录活性是通过控制 NF-kB二聚体从细胞质到细胞核。 一旦进入细胞核， 认为NF-kB二聚体与特定的DNA共有序列结合， 它们充当转录激活因子。 首席研究员介绍 有证据表明，核转位和DNA结合是 这是NF-kB转录活性所必需的，但不是足够的。 在欧共体， NF-kB的转录活性受到另外一种 信号通路涉及MAPK的活化，活化NF-kB二聚体 直接地或间接地。 具体来说，调查人员提供证据， RelA的转录活性依赖于 非典型蛋白激酶Czeta p21ras。 而且他们 目前的证据表明，cAMP依赖性蛋白激酶（PKA）具有 在EC中调节NF-κ B活性的双峰功能。 这是我们的目的 建议研究已鉴定的激酶模块，进一步鉴定激酶 参与NF-kB的磷酸化和激活，并确定 与RelA发生相互作用的激酶级联的确切水平。 通过解决这些具体目标，首席研究员希望 提供了关于转录调控的新见解， NF-κ B在EC中的活性及其对炎症的贡献。

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.