MMP-7 IN Pacreatic Cancer and Chronic Pancreatitis

MMP-7 在胰腺癌和慢性胰腺炎中的作用

基本信息

项目摘要

DESCRIPTION (provided by applicant): Pancreatic cancer is the 5th most common cause of cancer-related death in the United States, partly due to difficulties with early detection and partly due to its resistance to conventional cancer therapies. As such, an initiative has been put forth in the Program Research Group Report: "Pancreatic Cancer: An Agenda for Action" to encourage study of pancreatic tumor biology and reliable methods for detection and treatment. With this in mind, we have begun to explore some of the fundamental tumor biology of pancreatic cancer, focusing on the function and expression of matrix metalloproteinase-7 (MMP-7). It is known that epithelial metaplasia in the context of chronic pancreatitis (CP) increases the risk for pancreatic ductal adenocarcinoma (PDAC) by 16-50 fold. Matrix metalloproteinase-7 (MMP-7) is expressed in metaplastic duct-like epithelium in 93% and 100% of chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC) samples, respectively, and in tumor cells in 98% of PDAC samples. This striking association between MMP- 7 and pancreatic disease has led to the discovery that CP is severely inhibited in MMP-7 null mice, including an almost complete abrogation of ductal metaplasia. In this application, we propose to test the overall hypothesis that MMP-7 and proteins that regulate its expression are both necessary and sufficient to induce pancreatic ductal metaplasia, contributing to PDAC initiation and progression. Specifically, we will test if MMP-7 activity is necessary and sufficient for ductal metaplasia both in vitro. We will also analyze if MMP-7 function is necessary for PDAC formation, progression and invasion in mouse PDAC models. Finally, we will study the activity of two putative activators of MMP-7 expression, the pancreatic/duodenal homeobox protein (Pdx-1) and the AP-1 factor c-Jun, to study their ability to regulate MMP-7 and alter tumor cell behavior in immortal pancreatic duct cells and in human PDAC cell lines. We will also examine the role of Pdx-1 in regulating MMP-7 expression in mouse models of metaplasia in vivo. Overall, we expect these studies to contribute significantly to our knowledge of pancreatic tumor biology with immediate implications with regards to detection and treatment.
描述(由申请人提供):在美国,胰腺癌是癌症相关死亡的第五大常见原因,部分原因是早期检测困难,部分原因是其对传统癌症疗法的耐药性。因此,项目研究组报告“胰腺癌:行动议程”中提出了一项倡议,鼓励研究胰腺肿瘤生物学和可靠的检测和治疗方法。考虑到这一点,我们开始探索胰腺癌的一些基本肿瘤生物学,重点关注基质金属蛋白酶 7 (MMP-7) 的功能和表达。众所周知,慢性胰腺炎 (CP) 背景下的上皮化生会使胰腺导管腺癌 (PDAC) 的风险增加 16-50 倍。基质金属蛋白酶-7 (MMP-7) 分别在 93% 和 100% 的慢性胰腺炎和胰腺导管腺癌 (PDAC) 样本中的化生导管样上皮中表达,在 98% 的 PDAC 样本中的肿瘤细胞中表达。 MMP-7 与胰腺疾病之间的这种显着关联导致人们发现 CP 在 MMP-7 缺失小鼠中受到严重抑制,包括几乎完全消除导管化生。在本申请中,我们建议测试以下总体假设:MMP-7 和调节其表达的蛋白质对于诱导胰腺导管化生、促进 PDAC 的启动和进展都是必要且充分的。具体来说,我们将在体外测试 MMP-7 活性对于导管化生是否是必要和充分的。我们还将分析 MMP-7 功能是否是小鼠 PDAC 模型中 PDAC 形成、进展和侵袭所必需的。最后,我们将研究两种假定的 MMP-7 表达激活剂,即胰腺/十二指肠同源盒蛋白 (Pdx-1) 和 AP-1 因子 c-Jun 的活性,以研究它们调节 MMP-7 和改变永生胰管细胞和人 PDAC 细胞系中肿瘤细胞行为的能力。我们还将研究 Pdx-1 在小鼠体内化生模型中调节 MMP-7 表达的作用。总的来说,我们预计这些研究将极大地增进我们对胰腺肿瘤生物学的了解,并对检测和治疗产生直接影响。

项目成果

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Howard C Crawford其他文献

Howard C Crawford的其他文献

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{{ truncateString('Howard C Crawford', 18)}}的其他基金

Fibroblast orchestration of the immune response in pancreatic cancer
胰腺癌免疫反应的成纤维细胞协调
  • 批准号:
    10516238
  • 财政年份:
    2022
  • 资助金额:
    $ 24.1万
  • 项目类别:
Fibroblast orchestration of the immune response in pancreatic cancer
胰腺癌免疫反应的成纤维细胞协调
  • 批准号:
    10706561
  • 财政年份:
    2022
  • 资助金额:
    $ 24.1万
  • 项目类别:
Metaplastic Tuft Cells in Pancreatic Cancer
胰腺癌中的化生簇细胞
  • 批准号:
    10581696
  • 财政年份:
    2020
  • 资助金额:
    $ 24.1万
  • 项目类别:
Interrupting Cellular Crosstalk in the Immunosuppressive Microenvironment of Pancreas Cancer
中断胰腺癌免疫抑制微环境中的细胞串扰
  • 批准号:
    9449550
  • 财政年份:
    2017
  • 资助金额:
    $ 24.1万
  • 项目类别:
Interrupting Cellular Crosstalk in the Immunosuppressive Microenvironment of Pancreas Cancer
中断胰腺癌免疫抑制微环境中的细胞串扰
  • 批准号:
    10267780
  • 财政年份:
    2017
  • 资助金额:
    $ 24.1万
  • 项目类别:
Interrupting Cellular Crosstalk in the Immunosuppressive Microenvironment of Pancreas Cancer
中断胰腺癌免疫抑制微环境中的细胞串扰
  • 批准号:
    10242453
  • 财政年份:
    2017
  • 资助金额:
    $ 24.1万
  • 项目类别:
Discoidin Domain Receptors: Novel Players in Pancreatitis and Pancreatic Preneoplasia
盘状结构域受体:胰腺炎和胰腺癌前期的新参与者
  • 批准号:
    8811574
  • 财政年份:
    2014
  • 资助金额:
    $ 24.1万
  • 项目类别:
ADAM17 in pancreatic cancer and pancreatitis
ADAM17 在胰腺癌和胰腺炎中的作用
  • 批准号:
    8815948
  • 财政年份:
    2012
  • 资助金额:
    $ 24.1万
  • 项目类别:
ADAM17 in pancreatic cancer and pancreatitis
ADAM17 在胰腺癌和胰腺炎中的作用
  • 批准号:
    8608499
  • 财政年份:
    2012
  • 资助金额:
    $ 24.1万
  • 项目类别:
ADAM17 in pancreatic cancer and pancreatitis
ADAM17 在胰腺癌和胰腺炎中的作用
  • 批准号:
    8450710
  • 财政年份:
    2012
  • 资助金额:
    $ 24.1万
  • 项目类别:

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