Cellular Basis Of Action Of Gastrointestinal Peptides/Growth factors

胃肠肽/生长因子作用的细胞基础

基本信息

批准号：
8553518
负责人：
Robert Jensen
金额：
$ 66.7万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8553518
关键词：
Acinus organ component Area Bombesin Receptor Cell physiology Cells Cholecystokinin Cholecystokinin Receptor Collaborations Epidermal Growth Factor Receptor Focal Adhesion Kinase 1 Gastrointestinal Hormones Gastrointestinal tract structure Goals Growth Growth Factor Growth Factor Receptors Hormones Inflammatory Response Injury Japan Malignant neoplasm of lung Matrix Metalloproteinases Modeling Molecular Neuraxis PTK2B gene Pancreas Pancreatitis Peptides Play Process Protein Tyrosine Kinase Reactive Oxygen Species Receptor Activation Role Signal Transduction System Tissues Transactivation Tyrosine Phosphorylation base bombesin receptor subtype 3 cancer cell cell growth cell motility ds-DNA gastrointestinal neoplastic novel paxillin pituitary adenylate cyclase-activating peptide receptor receptor src-Family Kinases stellate cell tumor growth

项目摘要

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. .

最近的研究表明，胃肠激素/生长因子可能通过刺激多个细胞内酪氨酸磷酸化 (TyrP) 信号级联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的能力知之甚少。我们的研究主要集中在两个领域，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以及试图开发新的生长抑制药物的肿瘤生长的研究。最近的研究表明，胃肠激素与生长因子类似，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通过生长因子进行了广泛的研究，但在这一领域对胃肠激素的了解却很少。这些研究的目的是阐明这一领域，主要集中于胆囊收缩素受体级联和铃蟾肽受体激活，主要使用胰腺腺泡作为自然细胞系统模型，并研究胃肠激素在刺激肿瘤生长（主要是肺癌）中的作用。在四项不同的研究中，发现肺癌细胞上 Bn 相关受体 (BRS-3) 以及 PACAP 受体的激活可刺激肿瘤生长，其机制涉及 EGF 受体的反式激活以及刺激 p125FAK、桩蛋白和 PYK2 的激活除了活性氧、基质金属蛋白酶和 Src 的激活之外。在胰腺腺泡中，CCK 和其他 PLC 激活激素被证明可以激活 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发挥重要作用。与日本福冈的 Ito 教授合作，胞质双链 DNA 显示出一种与损伤相关的分子模式，可诱导胰腺星状细胞中的炎症反应，并且是组织损伤相关胰腺炎的一种可能机制。。