Cellular Basis Of Action Of Gastrointestinal Peptides/Growth factors

胃肠肽/生长因子作用的细胞基础

• 批准号: 8741483
• 负责人: Robert Jensen
• 金额: $ 71.25万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 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/8741483
• 关键词: Adverse effects; Agonist; Area; Bombesin; Bombesin Receptor; CXCL1 gene; Cell physiology; Collaborations; Diabetes Mellitus; Epidermal Growth Factor Receptor; Family; Fatty acid glycerol esters; Focal Adhesion Kinase 1; Fractalkine; G-Protein-Coupled Receptors; GCG gene; Gastrointestinal Hormones; Gastrointestinal tract structure; Growth; Growth Factor; Growth Factor Receptors; Inflammatory Response; Injury; Insulin; Japan; Lead; MAP Kinase Gene; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Matrix Metalloproteinases; Metabolism; Metalloproteases; Molecular; Muscle Cells; Neuraxis; Neurotensin; Obesity; Orphan; PTK2B gene; Pancreas; Pancreatitis; Pattern; Peptides; Pharmacology; Process; Protein Tyrosine Kinase; Reactive Oxygen Species; Role; SLC2A1 gene; Signal Transduction; Spain; Tissues; Transactivation; Tyrosine Phosphorylation; autocrine; base; bombesin receptor subtype 3; cancer cell; cancer therapy; cell growth; cell motility; cytokine; diabetic; ds-DNA; gastrointestinal; glucose transport; insight; member; neoplastic; neoplastic cell; novel; paxillin; pituitary adenylate cyclase activating polypeptide; receptor; relating to nervous system; stellate cell

Recent studies show that gastrointestinal hormones/growth factors may cause 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. In a study on lung cancer cells we investigated the ability of the G-protein coupled receptors for PACAP/VIP to stimulate their growth. We found that the mechanism involved transactivation of the EGF receptor as well as stimulating activation of focal adhesion kinase, paxillin and PYK2, in addition to activation of reactive oxygen species, matrix metalloproteinases and Src. Similar studies are now underway investigating the ability of the GI-neural peptide neurotensin, to stimulate growth of these cells in an autocrine manner as well as the orphan receptor BRS-3, a member of the bombesin receptor family (BN-R). Bombesin-related peptides are particularly important autocrine growth factors for these cancers, and many others, however, many tumor cells posses multiple BN-R receptor subtypes, and the role of the BRS-3 receptor has not be studied until now. With the availability highly selective BRS-3 agonists/antagonists (discussed in pharmacology section) we are now able to perform these studies. Insights from these studies many lead to novel treatments for these cancers. In collaboration with Dr N.Gonzalez(Madrid, Spain) we explored the cellular mechanisms by which the BnR receptor, BRS-3 regulates fat and insulin metabolism. BRS-3 signaling was investigated in dispersed myocytes form normal, obese, or diabetic subjects. Marked differences were found in these different myocytes in the ability of BRS-3 agonists to stimulate GLUT-4 levels, glucose transport, and activate the PI3K signaling cascades, demonstrating alterations in BRS-3 signaling are important in the changes seen in diabetes and obesity. Pancreatic stellate cells are important in both pancreatitis and pancreatic cancer and they are activated by a number of cytokines and G-protein coupled receptors however little is known of their signaling or importance in causing pancreatitis. Three studies in collaboration with Prof Ito, Fukuoka, Japan were performed investigating their signaling in pancreatitis. In one study almost completed, receptors for the GLP1 were found on stellate cells. This could be particularly important because these agents are widely used to treat diabetes and one of their unwanted side-effect is pancreatitis, the mechanism of which is unknown. We found GLP1R receptor increase in number during pancreatitis, in the stellate cells, they activate the MAPK cascade and can cause growth of these cells suggesting they may be involve in this side-effect of GLP1-R usage In another study, the role of the cytokine fractalkine (CXCL1) in pancreatitis was investigate and it was found to be secreted by stellate cells though a MPK mechanism involving metalloproteinase, and this could contribute to the role of stellate cells signaling in causing pancreatitis. In a final study cytosolic double-stranded DNA was shown to show a damage-associated molecular pattern 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）信号级联以及通过反式激活生长因子受体而导致细胞生长。但是，目前对许多胃肠道激素/生长因子激活这些级联反应的能力知之甚少。在一项关于肺癌细胞的研究中，我们研究了G蛋白偶联受体对PACAP/VIP刺激其生长的能力。我们发现，除了激活活性氧，基质金属蛋白酶和SRC外，除了激活焦点粘附激酶，paxillin和pyk2外，涉及EGF受体的反式激活以及刺激局灶性粘附激酶的激活。现在正在进行类似的研究，研究了Gi-nur肽神经素的能力，以自分泌方式以及bombesin受体家族（BN-R）成员的孤儿受体BRS-3刺激这些细胞的生长。对于这些癌症而言，与孟买相关的肽是特别重要的自分泌生长因子，而许多其他癌症则具有多种BN-R受体亚型，并且直到现在尚未研究BRS-3受体的作用。借助高度选择性的BRS-3激动剂/拮抗剂（在药理学部分进行了讨论），我们现在能够进行这些研究。 这些研究的见解许多导致了这些癌症的新型治疗方法。 与N.Gonzalez博士（西班牙马德里）合作，我们探讨了BNR受体BRS-3调节脂肪和胰岛素代谢的细胞机制。 BRS-3信号在分散的心肌细胞中进行了正常，肥胖或糖尿病患者的研究。在这些不同的肌细胞中发现了明显的差异，这在BRS-3激动剂刺激Glut-4水平，葡萄糖转运和激活PI3K信号级联反应的能力中发现了明显的差异，这表明BRS-3信号传导的变化对于糖尿病和肥胖症中看到的变化很重要。 胰腺星状细胞在胰腺炎和胰腺癌中都很重要，并且被多种细胞因子和G蛋白偶联受体激活，但是对引起胰腺炎的信号传导或重要性知之甚少。与日本福库卡（Fukuoka）的ITO合作进行了三项研究，研究了其在胰腺炎中的信号传导。在一项几乎完成的研究中，在星状细胞上发现了GLP1的受体。这可能尤其重要，因为这些药物被广泛用于治疗糖尿病，其不良副作用之一是胰腺炎，其机制尚不清楚。 We found GLP1R receptor increase in number during pancreatitis, in the stellate cells, they activate the MAPK cascade and can cause growth of these cells suggesting they may be involve in this side-effect of GLP1-R usage In another study, the role of the cytokine fractalkine (CXCL1) in pancreatitis was investigate and it was found to be secreted by stellate cells though a MPK mechanism involving金属蛋白酶，这可能有助于星状细胞信号传导在引起胰腺炎中的作用。在最终的研究中，胞质双链DNA显示出与损伤相关的分子模式，该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。 。