PKD1 signaling in the initiation of pancreatic cancer

 描述(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)的转化分化是导致胰腺上皮内瘤变(Panin)和胰腺癌发展的第一步。ADM可在激活表皮生长因子受体、获得激活突变的Kras和巨噬细胞分泌的细胞因子后启动。然而，这些诱导物下游驱动ADM的共同信号机制在很大程度上尚不清楚。我们的假设是，PKD1信号的激活是腺泡到导管化生诱导物的共同特征，推动了Panins的形成和胰腺肿瘤的进展。为了验证这一点，我们将：确定PKD1的激活是否是不同ADM诱导者的共同机制(特定目标1)；确定驱动ADM和形成管状胰祖细胞的PKD1下游信号通路(特定目标2)；确定是否表达和/或 PKD1的活性表明ADM在体内向Panins和PDA的进展(特异性目标3)；并使用遗传动物模型来确定PKD1在胰腺癌发生发展中的作用(特异性目标4)。我们的项目的成功完成将确定PKD1是启动胰腺癌发展的过程的共同特征。它还将定义PKD1上下游的信号事件，这些信号事件促进Panin的形成，并有助于胰腺癌的发展。早期诊断和早期靶向是胰腺癌介入治疗成功的关键。我们的结果将为两者提供基础，因为PKD1是一种靶向激酶，可以作为早期事件的分子信号标志物。

 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.