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PKD1 signaling in the initiation of pancreatic cancer

PKD1 信号在胰腺癌发生过程中的作用

基本信息

批准号：
10062875
负责人：
Peter Storz
金额：
$ 14.58万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10062875
关键词：
3-Dimensional Acinar Cell Animal Genetics Animal Model Applications Grants Automobile Driving Cells Clinical Cyclic AMP-Dependent Protein Kinases Data Development Diagnosis Disease Duct (organ) structure Early Diagnosis Epidermal Growth Factor Receptor Event Generations Genetic Goals Human In Vitro KRASG12D Knock-out Lesion Malignant neoplasm of pancreas Mediating Metaplasia Modeling Molecular Morphology Mus Mutation Nuclear Organoids Outcome Oxidative Stress Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pancreatic duct Phosphotransferases Prevention Process Protein Analysis Protein Kinase Protein-Serine-Threonine Kinases RANTES Reactive Oxygen Species Role Signal Pathway Signal Transduction Structure TNF gene Testing Transgenic Mice Up-Regulation Work activating transcription factor base cancer initiation cell type cytokine in vivo islet stem cells macrophage molecular targeted therapies mouse model neoplastic notch protein pancreas development pancreatic metaplasia pancreatic neoplasm predictive marker premalignant protein activation public health relevance sensor stem cells successful intervention transdifferentiation tumor

项目摘要

DESCRIPTION (provided by applicant): The trans differentiation of pancreatic acinar cells to a duct-like, pluripotent progenitor cell type (ADM, acinar-to- ductal metaplasia) is an initial step leading to the development of pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer. ADM can be initiated after activation of the epidermal growth factor receptor, acquisition of activating mutations of Kras and macrophage-secreted cytokines. However, the common signaling mechanism driving ADM downstream of these inducers are largely unknown. It is our hypothesis that activation of a PKD1 signaling is a common feature of inducers of acinar-to-ductal metaplasia, driving the formation of PanINs and the progression to pancreatic tumors. To test this we will: Determine if activation of PKD1 is a common mechanism for different inducers of ADM (Specific Aim 1); identify PKD1 downstream signaling pathways that drive ADM and the formation of duct-like pancreatic progenitor cells (Specific Aim 2); determine if expression and/or activity of PKD1 indicate progression of ADM to PanINs and PDA in vivo (Specific Aim 3); and use genetic animal models to define the role of PKD1 in development of pancreatic cancer (Specific Aim 4). Successful completion of our project will identify PKD1 as a common feature of processes that initiate the development of pancreatic cancer. It also will define the signaling events up- and downstream of PKD1 that facilitate PanIN formation and contribute to development of pancreatic cancer. Early diagnosis and early targeting are key for successful intervention of pancreatic cancer. Our results will provide the basis for both, since PKD1 is a targetable kinase and can be a molecular signaling marker for early events.

描述（由申请人提供）：胰腺腺泡细胞向导管样多能祖细胞类型（ADM，腺泡到导管化生）的转分化是导致胰腺上皮内瘤变（PanIN）和胰腺癌发展的第一步。 ADM 可以在表皮生长因子受体激活、获得 Kras 激活突变和巨噬细胞分泌的细胞因子后启动。然而，驱动这些诱导剂下游 ADM 的常见信号机制在很大程度上尚不清楚。我们假设 PKD1 信号传导的激活是腺泡导管化生诱导剂的共同特征，驱动 PanIN 的形成和胰腺肿瘤的进展。为了测试这一点，我们将：确定 PKD1 的激活是否是不同 ADM 诱导剂的常见机制（具体目标 1）；确定驱动 ADM 和导管样胰腺祖细胞形成的 PKD1 下游信号通路（具体目标 2）；确定表达式和/或 PKD1 的活性表明体内 ADM 进展为 PanIN 和 PDA（具体目标 3）；并使用遗传动物模型来定义 PKD1 在胰腺癌发展中的作用（具体目标 4）。我们项目的成功完成将确定 PKD1 是引发胰腺癌发展过程的一个共同特征。它还将定义 PKD1 上游和下游的信号转导事件，促进 PanIN 形成并有助于胰腺癌的发展。早期诊断和早期靶向是成功干预胰腺癌的关键。我们的结果将为两者提供基础，因为 PKD1 是一种可靶向激酶，并且可以作为早期事件的分子信号标记。