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; 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.

胰腺癌将是所有癌症在2030年的第二大死亡原因。除其他癌症外，慢性胰腺炎是胰腺癌发展的危险因素，在遗传性慢性胰腺炎中，风险增加最高。在过去的几十年中，已经描述了慢性胰腺炎的几个遗传关联，例如在阳离子胰蛋白酶原基因（PRSS1）或丝氨酸蛋白酶抑制剂1型Kazal 1型（Spink1）中进行突变。 2013年，据报道，羧肽酶A1（CPA1）的突变与疾病早期发作的新型关联。最近，产生了一种新型的慢性胰腺炎动物模型，该模型构成了常见的P.N256K突变的敲打，并具有慢性胰腺炎的自发表型。该模型是进一步阐明癌变中炎症提示的早期机制的理想选择，为此，我们将CPA1N256K与KRASG12D突变小鼠（KC）杂交了CPA1N256K（KC），以产生胰腺癌发育的新型模型。在此模型中，我们将重点关注体内和原代腺泡细胞中的早期腺泡事件，以及在鼠胰腺panin细胞中过度表达突变的CPA1。实验将集中于内质网应激引起的事件以及在转录和蛋白质水平上与胰腺癌发育相关的已知途径和免疫表型。长期确定的途径或免疫表型将被针对防止肿瘤基质和肿瘤发育的发展。