Cellular Basis Of Action Of Gastrointestinal Peptides/Growth factors

最近的研究表明，胃肠激素/生长因子可以通过刺激多个细胞内酪氨酸磷酸化（TyrP）信号级联以及通过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的能力知之甚少。 我们的研究主要集中在两个方面，其中包括主要通过酪氨酸激酶进行的细胞内信号级联的研究和试图开发新的生长抑制剂的肿瘤生长研究。最近的研究表明，胃肠激素，类似于生长因子，可以通过刺激多个细胞内酪氨酸磷酸化（TyrP）级联来刺激细胞生长/细胞信号传导。虽然这些级联反应已被广泛研究与生长因子，很少有人知道在这方面与胃肠道激素。这些研究的目的是澄清这一领域主要集中在胆囊收缩素受体级联和蛙皮素受体活化，主要使用胰腺腺泡作为模型天然细胞系统。进行了涉及激动剂刺激Bn相关孤儿受体、BRS-3刺激肺癌细胞或BRS-3转染细胞生长的能力的研究。这些研究表明，BRS-3激活刺激EGF受体的反式激活，这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p125 FAK和paxillin酪氨酸磷酸化，这两个重要的对接蛋白调节细胞的运动、粘附和生长。 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 θ，并在激活其他关键信号级联中发挥重要作用。与日本福冈的Ito教授合作，VIP通过抑制NADPH氧化酶来抑制氧化应激，从而部分改善实验性胰腺炎。

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.