Cellular Basis Of Action Of Gastrointestinal Peptides/Growth factors

最近的研究表明，胃肠激素/生长因子可能通过刺激细胞内多个酪氨酸磷酸化(TyrP)信号通路以及反式激活生长因子受体来刺激细胞生长。然而，目前对许多胃肠激素/生长因子激活这些级联反应的能力知之甚少。我们的研究主要集中在两个方面，包括主要通过酪氨酸激酶的细胞内信号级联反应的研究和试图开发新的生长抑制药物的肿瘤生长研究。最近的研究表明，胃肠激素类似于生长因子，可能通过刺激细胞内多个酪氨酸磷酸化(TyrP)级联来刺激细胞生长/细胞信号转导。虽然这些级联反应已经用生长因子进行了广泛的研究，但对这一领域的胃肠激素却知之甚少。这些研究的目的是阐明这一领域，主要集中在以胰腺腺泡为模型的自然细胞系统中，研究胆囊收缩素受体的级联和蛙皮素受体的激活。研究了激动剂刺激Bn相关孤儿受体BRS-3刺激肺癌细胞或BRS-3转基因细胞生长的能力。这些研究表明，BRS-3的激活刺激了EGF受体的反式激活，这种反式激活依赖于基质金属蛋白酶的激活和活性氧的产生。相关研究表明，PACAP受体在多种细胞中的激活导致p125FAK和Paxlin酪氨酸磷酸化，这两种蛋白是调节细胞运动、黏附和生长的两个重要对接蛋白。在胰腺腺泡中，CCK和其他PLC激活激素首次被证明激活新的PKC、PKC theta，它在激活其他关键信号级联中发挥重要作用。在与日本福冈的伊藤教授的合作中，VIP被证明通过抑制NADPH氧化酶来抑制氧化应激，从而部分缓解实验性胰腺炎。

Recent studies show that gastrointestinal hormones/growth factors may stimulate cell growth by stimulating multiple intracellular tyrosine phosphorylation (TyrP) signaling cascades as well as by transactivating growth factor receptors. However at present little is known about the ability of many gastrointestinal hormones/growth factors to activate these cascades. Our studies have been in two general areas, which include studies of intracellular signaling cascades primarily by tyrosine kinases and studies of tumoral growth attempting to develop novel agents for growth inhibition. Recent studies show that gastrointestinal hormones, similar to growth factors, may stimulate cell growth/cell signaling by stimulating multiple intracellular tyrosine phosphorylation (TyrP) cascades. Whereas these cascades have been extensively investigated with growth factors, little is known in this area with may gastrointestinal hormones. The goal of these studies is to clarify this area primarily concentrating on cholecystokinin receptor cascades and bombesin receptor activation using primarily pancreatic acini as a model natural cell system. Studies involving the ability of agonists to stimulate the Bn related orphan receptor, BRS-3 to stimulate growth of lung cancer cells or BRS-3 transfected cells were performed. These studies show that BRS-3 activation stimulates transactivation of the EGF receptor which is dependent on activation of matrix metalloproteinases and the generation of reactive oxygen species. Related studies demonstrated the PACAP receptor activation in various cells results in p125FAK and paxillin tyrosine phosphorylation, two important docking proteins regulating cell motility, adhesion and important in growth. In pancreatic acini, CCK and other PLC activating hormones was shown to activate the novel PKC, PKC theta for the first time and it to play an important role in activating other key signaling cascades. In collaboration with Prof Ito, Fukuoka, Japan, VIP was shown to partially ameliorate experimental pancreatitis by inhibiting oxidative stress through the inhibition of NADPH oxidase.