The interface of pancreatitis and early pancreatic cancer progression – In depth analysis of the novel, spontanous pancreatic cancer mouse model Cpa1 N256K – KC

胰腺炎与早期胰腺癌进展的界面 â 深入分析新型自发性胰腺癌小鼠模型 Cpa1 N256K â KC

• 批准号: 504677297
• 负责人: Professor Dr. Jonas Rosendahl
• 金额: --
• 依托单位: Universitätsklinik und Poliklinik für Innere Medizin I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/504677297?language=en
• 关键词: interface; pancreatitis; early; pancreatic; cancer

Pancreatic cancer will be the second most common cause of death of all cancers in 2030. Amongst others chronic pancreatitis is a risk factor for the development of pancreatic cancer and the risk increase is highest in inherited chronic pancreatitis. In the last decades several genetic associations in chronic pancreatitis have been described for example with mutations in the cationic trypsinogen gene (PRSS1) or the serine protease inhibitor, Kazal type 1 (SPINK1). In 2013 a novel association with mutations in carboxypeptidase A1 (CPA1) with an early onset of the disease was reported. Recently, a novel animal model of chronic pancreatitis harbouring a knock in of the common p.N256K mutation was generated and presented with a spontaneous phenotype of chronic pancreatitis. This model is ideal to further elucidate the early mechanisms of inflammatory cues in carcinogenesis and for this purpose we crossbred Cpa1N256K with KrasG12D mutated mice (KC) to generate a novel model of pancreatic cancer development. In this model we will focus on early acinar events in vivo and in primary acinar cells as well as by overexpression of mutated CPA1 in murine pancreatic PanIN cells. The experiments will focus on events induced by endoplasmatic reticulum stress and on known pathways and immune phenotypes relevant for pancreatic cancer development on the level of the transcriptom and proteom. On the long-term identified pathways or immune phenotypes will be targeted to prevent the development of tumour stroma and tumour development.

到2030年，胰腺癌将成为所有癌症中第二大常见死因。在其他疾病中，慢性胰腺炎是胰腺癌发展的一个危险因素，而遗传性慢性胰腺炎的风险增加最高。在过去的几十年里，慢性胰腺炎的一些遗传关联已经被描述，例如阳离子胰蛋白酶原基因（PRSS1）或丝氨酸蛋白酶抑制剂Kazal型1 （SPINK1）的突变。2013年，有报道称羧基肽酶A1 （CPA1）突变与该疾病的早期发病有新的关联。最近，一种新的慢性胰腺炎动物模型产生了常见的p.N256K突变的敲入，并呈现出慢性胰腺炎的自发表型。该模型是进一步阐明炎症线索在癌变中的早期机制的理想模型，为此，我们将Cpa1N256K与KrasG12D突变小鼠（KC）杂交，以产生一种新的胰腺癌发展模型。在这个模型中，我们将关注体内和原代腺泡细胞中的早期腺泡事件，以及小鼠胰腺PanIN细胞中突变CPA1的过表达。实验将集中在内质网应激诱导的事件，以及转录和蛋白质组水平上与胰腺癌发展相关的已知途径和免疫表型。对长期确定的途径或免疫表型将有针对性地防止肿瘤基质的发展和肿瘤的发展。