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

项目摘要

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)信号级联以及反式激活生长因子受体来引起细胞生长。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。在一项针对肺癌细胞的研究中,我们研究了 PACAP/VIP 的 G 蛋白偶联受体刺激其生长的能力。我们发现该机制涉及 EGF 受体的反式激活以及刺激粘着斑激酶、桩蛋白和 PYK2 的激活,以及活性氧、基质金属蛋白酶和 Src 的激活。目前正在进行类似的研究,研究胃肠道神经肽神经降压素以及孤儿受体 BRS-3(铃蟾肽受体家族 (BN-R) 的成员)以自分泌方式刺激这些细胞生长的能力。铃蟾肽相关肽对于这些癌症和许多其他癌症来说是特别重要的自分泌生长因子,然而,许多肿瘤细胞具有多种 BN-R 受体亚型,并且 BRS-3 受体的作用迄今为止尚未被研究。凭借高度选择性的 BRS-3 激动剂/拮抗剂(在药理学部分讨论),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疗法。 我们与 N.Gonzalez 博士(西班牙马德里)合作,探索了 BnR 受体 BRS-3 调节脂肪和胰岛素代谢的细胞机制。在正常、肥胖或糖尿病受试者的分散肌细胞中研究了 BRS-3 信号传导。在这些不同的肌细胞中,BRS-3 激动剂刺激 GLUT-4 水平、葡萄糖转运和激活 PI3K 信号级联的能力存在显着差异,这表明 BRS-3 信号传导的改变对于糖尿病和肥胖症的变化非常重要。 胰腺星状细胞在胰腺炎和胰腺癌中都很重要,它们被许多细胞因子和 G 蛋白偶联受体激活,但人们对它们的信号传导或引起胰腺炎的重要性知之甚少。与日本福冈的伊藤教授合作进行了三项研究,调查它们在胰腺炎中的信号传导。在一项即将完成的研究中,在星状细胞上发现了 GLP1 受体。这可能特别重要,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。我们发现,在胰腺炎期间,星状细胞中的 GLP1R 受体数量增加,它们激活 MAPK 级联反应,并可导致这些细胞的生长,表明它们可能参与了 GLP1-R 使用的副作用。在另一项研究中,GLP1R 受体的作用研究人员对胰腺炎中的细胞因子 fractalkine (CXCL1) 进行了研究,发现它是通过涉及金属蛋白酶的 MPK 机制由星状细胞分泌的,这可能有助于星状细胞信号传导在胰腺炎中的作用。引起胰腺炎。在最终研究中,胞浆双链 DNA 显示出一种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。 。

项目成果

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Robert Jensen其他文献

Robert Jensen的其他文献

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{{ truncateString('Robert Jensen', 18)}}的其他基金

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:
    8553518
  • 财政年份:
  • 资助金额:
    $ 71.25万
  • 项目类别:
Characterization And Pharmacology Of Receptors For Gastrointestinal Peptides
胃肠肽受体的表征和药理学
  • 批准号:
    8349811
  • 财政年份:
  • 资助金额:
    $ 71.25万
  • 项目类别:
Diagnosis, Natural History, Management,tumor biology of Gastrinomas/PETs/Neuroendocrine tumors
胃泌素瘤/PET/神经内分泌肿瘤的诊断、自然史、治疗、肿瘤生物学
  • 批准号:
    10260271
  • 财政年份:
  • 资助金额:
    $ 71.25万
  • 项目类别:
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:
    7593651
  • 财政年份:
  • 资助金额:
    $ 71.25万
  • 项目类别:
Characterization And Pharmacology Of Receptors For Gastrointestinal Peptides
胃肠肽受体的表征和药理学
  • 批准号:
    7593650
  • 财政年份:
  • 资助金额:
    $ 71.25万
  • 项目类别:
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:
    10932755
  • 财政年份:
  • 资助金额:
    $ 71.25万
  • 项目类别:
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:
    10493931
  • 财政年份:
  • 资助金额:
    $ 71.25万
  • 项目类别:
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:
    7967526
  • 财政年份:
  • 资助金额:
    $ 71.25万
  • 项目类别:
Diagnosis, Natural History, Management and tumor biology of Gastrinomas
胃泌素瘤的诊断、自然史、治疗和肿瘤生物学
  • 批准号:
    7967528
  • 财政年份:
  • 资助金额:
    $ 71.25万
  • 项目类别:
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:
    8349812
  • 财政年份:
  • 资助金额:
    $ 71.25万
  • 项目类别:

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