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，以及研究胃肠激素在刺激肿瘤生长（主要是肺癌）的作用。在四项不同的研究中，发现肺癌细胞上的BN相关受体（BRS-3）以及PACAP受体的激活刺激肿瘤生长，并且机制涉及EGF受体的反式激活以及除了活性氧物质、基质金属蛋白酶和Src的激活之外刺激p125 FAK、桩蛋白和PYK 2的激活。 在胰腺腺泡中，CCK和其他PLC激活激素被证明激活Src激酶YES，并且其激活在激活CCK刺激的其他关键信号级联中起重要作用。与日本福冈的Ito教授合作，细胞溶质双链DNA显示出损伤相关的分子模式，诱导胰腺星状细胞的炎症反应，并成为组织损伤相关胰腺炎的合理机制。.

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 as well as to study the role of gastrointestinal hormones in stimulating tumor growth(primarily lung cancer ). In four different studies activation of Bn-related receptors (BRS-3) as well as PACAP receptors on lung cancer cells were found to stimulate tumor growth and the mechanism involved transactivation of the EGF receptor as well as stimulating activation of p125FAK, paxillin and PYK2 in addition to activation of reactive oxygen species, matrix metalloproteinases and Src. In pancreatic acini, CCK and other PLC activating hormones was shown to activate the Src kinase YES and its activation to play an important role in activating other key signaling cascades stimulated by CCK. In collaboration with Prof Ito, Fukuoka, Japan, cytosolic double-stranded DNA was shown to show a damage-associated molecular patten that induced the inflammatory response in pancreatic stellate cells and to be a plausible mechanism for tissue injury-associated pancreatitis. .