Characterizing the fibrogenic role of NADPH oxidase 1 in the transition from chronic pancreatitis to pancreatic cancer

表征 NADPH 氧化酶 1 在慢性胰腺炎向胰腺癌转变中的纤维形成作用

基本信息

  • 批准号:
    10515175
  • 负责人:
  • 金额:
    $ 44.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-08-01 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT The problem: Patients suffering from chronic pancreatitis (CP) have a higher risk of pancreatic ductal adenocarcinoma (PDAC). CP is characterized by an activated pancreatic stellate cell (PaSC)-rich stroma, which has facilitated the progression of non-invasive PanIN lesions to invasive PDAC. A critical barrier to progress in preventing the CP-to-PDAC transition is the gap of knowledge regarding the mechanism by which quiescent PaSCs become activated by inflammatory mediators, expand, and synthesize stroma and matrix metalloproteinases (MMPs), facilitating the progression of non-invasive PanIN lesions to invasive PDAC. Among the inflammatory mediators of CP are reactive oxygen species (ROS), which activate PaSCs. ROS generation can occur as a primary product of NADPH oxidase (Nox) enzymes. Previously, we showed that Nox1 signaling in CP-activated PaSCs: i) forms fibrotic tissue, ii) up-regulates both the transcription factor E-cadherin repressor Twist1 and MMP-9, and iii) facilitates the invasion of pancreatic cancer cell lines both in vitro and in vivo. The objective: To address the gaps in our knowledge regarding the mechanisms by which Nox1/Twist1/MMP-9 signaling in CP-activated PaSCs facilitates the progression of non-invasive PanIN lesions to invasive PDAC. The central hypothesis: The induction of CP generates ROS by Nox1 in PaSCs, which lead to a sustained expression of Twist1. Twist1, in turn, induces the expression of MMP-9, which promotes the progression of non- invasive PanIN lesions to invasive PDAC by degrading the basal lamina. The hypothesis will be tested by pursuing two specific aims: 1) Under the first aim, we will test in vitro the prediction that inhibiting Nox1/Twist1/MMP-9 signaling in CP-activated PaSCs attenuates the degradation of collagen IV and laminin. Under the second aim, we will test in vivo the prediction that inhibiting Nox1 signaling in CP-activated PaSCs prevents the progression of non-invasive PanIN lesions to invasive PDAC by attenuating the degradation of basal lamina. Our outcomes will include 1) new knowledge of CP-related mechanisms of progression of PDAC, 2) new knowledge of Nox1-related mechanisms of progression of PDAC, 3) high impact research experiences for undergraduate students. The approach is innovate because it will assess the extent to which the generation of Nox1-derived ROS from CP-activated PaSCs can facilitate the progression of non-invasive PanIN lesions to invasive PDAC. The proposed research is significant because a finding that the lack of Nox1 in CP-activated PaSCs prevents the progression of PanIN lesions to invasive PDAC by attenuating the degradation of basal lamina will establish the feasibility and premise for future translational research directed at developing rational, stroma-targeted therapies of early-stages of PDAC (e.g., carcinoma in situ) that, in combination with other approaches might lead to clinical strategies to increase the survival of patients. Moreover, these studies are designed to promote opportunities for a diverse undergraduate student participation providing them with exposure to hands-on experiments and close mentoring.
项目总结/摘要 问题:患有慢性胰腺炎(CP)的患者有更高的胰腺导管炎风险。 腺癌(PDAC)。CP的特征在于富含活化的胰腺星状细胞(PaSC)的基质, 促进了非侵袭性PanIN病变进展为侵袭性PDAC。阻碍进步的关键障碍 在防止CP到PDAC的过渡是知识的差距,有关的机制, PaSC被炎症介质激活,扩张并合成基质和基质 金属蛋白酶(MMPs),促进非侵袭性PanIN病变进展为侵袭性PDAC。之间 CP的炎症介质是活性氧(ROS),其激活PaSC。ROS生成 可作为NADPH氧化酶(Nox)酶的初级产物发生。之前,我们发现Nox 1信号 在CP激活的PaSC中:i)形成纤维化组织,ii)上调转录因子E-钙粘蛋白阻遏物 Twist 1和MMP-9,和iii)促进胰腺癌细胞系在体外和体内的侵袭。的 目的:填补我们对Nox 1/Twist 1/MMP-9的作用机制的知识空白, CP激活的PaSC中的信号传导促进非侵入性PanIN损伤进展为侵入性PDAC。 核心假设:CP的诱导通过PaSC中的Nox 1产生ROS,这导致持续的 Twist 1的表达。反过来,Twist 1诱导MMP-9的表达,MMP-9促进了非肿瘤细胞的进展。 通过降解基底膜将侵袭性PanIN病变转化为侵袭性PDAC。该假设将通过以下方式进行检验: 追求两个具体目标:1)在第一个目标下,我们将在体外测试抑制 CP激活的PaSCs中的Nox 1/Twist 1/MMP-9信号转导减弱IV型胶原和层粘连蛋白的降解。 在第二个目标下,我们将在体内测试在CP激活的PaSC中抑制Nox 1信号传导的预测, 通过减弱非侵袭性PanIN病变的降解, 基底层我们的成果将包括1)对PDAC进展的CP相关机制的新认识, 2)PDAC进展的Nox 1相关机制的新知识,3)高影响力的研究经验 对于本科生来说。这种方法是创新的,因为它将评估一代人在多大程度上 来自CP激活的PaSC的Nox 1衍生的ROS可以促进非侵入性PanIN病变的进展, 侵入性PDAC。这项研究是有意义的,因为一项发现表明,在CP激活的 PaSC通过减弱基础胰岛素的降解,防止PanIN病变进展为侵袭性PDAC。 lamina将为未来的翻译研究建立可行性和前提, 基质靶向治疗 早期阶段 PDAC(例如, 原位癌) 这一点与其他 这些方法可能会导致临床策略,以提高患者的生存率。此外,这些研究 旨在促进多样化的本科生参与的机会,为他们提供 接触动手实验和密切指导。

项目成果

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Maria Eugenia Sabbatini其他文献

The Role of Twist1 in Chronic Pancreatitis–Associated Pancreatic Stellate Cells
Twist1在慢性胰腺炎相关胰腺星状细胞中的作用
  • DOI:
    10.1016/j.ajpath.2024.06.003
  • 发表时间:
    2024-10-01
  • 期刊:
  • 影响因子:
    3.600
  • 作者:
    Emma Geister;Dalton Ard;Heer Patel;Alyssa Findley;Godfrey DeSouza;Lyndsay Martin;Henry Knox;Natasha Gavara;Aurelia Lugea;Maria Eugenia Sabbatini
  • 通讯作者:
    Maria Eugenia Sabbatini

Maria Eugenia Sabbatini的其他文献

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