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：
9187443
负责人：
Peter Storz
金额：
$ 35.8万
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 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9187443
关键词：
Acinar Cell Animal Genetics Animal Model Applications Grants Automobile Driving Cells Clinical Cyclic AMP-Dependent Protein Kinases Data Development Diagnosis Disease Duct (organ) structure Ductal Early Diagnosis Epidermal Growth Factor Receptor Event Generations Genetic Goals Human In Vitro 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 Premalignant Prevention Process Protein Analysis Protein Kinase Protein-Serine-Threonine Kinases RANTES Reactive Oxygen Species Role Signal Pathway Signal Transduction Stem cells Structure TNF gene Testing Transgenic Mice Up-Regulation Work activating transcription factor base cancer initiation cell type cytokine in vivo macrophage molecular targeted therapies mouse model neoplastic notch protein pancreas development pancreatic neoplasm predictive marker protein activation public health relevance sensor 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（由适用提供）：胰腺腺泡细胞的反式分化向类似管道样的多能祖细胞类型（ADM，腺泡到外向化生）是导致胰腺内上皮内部肿瘤（Panin）和胰腺癌发展的初步步骤。在激活表皮生长因子受体，获得KRAS和巨噬细胞分泌的细胞因子的激活突变后，可以启动ADM。但是，这些诱导剂下游驱动ADM的常见信号传导机制在很大程度上是未知的。我们的假设是，PKD1信号传导的激活是腺泡到导管化生的诱导者的共同特征，驱动Panins的形成和胰腺肿瘤的发展。为了测试这一点，我们将：确定PKD1的激活是否是不同诱导剂的常见机制（特定目标1）；识别驱动ADM的PKD1信号通路和导管样胰腺祖细胞的形成（特定的AIM 2）；确定是否表达和/或 PKD1的活性表明panins和PDA在体内的进展（特定目标3）；并使用遗传动物模型来定义PKD1在胰腺癌发展中的作用（特定目标4）。成功完成我们的项目将确定PKD1是启动胰腺癌发展的过程的共同特征。它还将在PKD1的上游定义信号事件，从而促进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是一种靶向激酶，并且可以是早期事件的分子信号标记。