胰腺癌（PDAC）具有不易早期诊断且多药耐药的特点。相对于正常细胞对内质网应激（ER stress）敏感，PDAC利用ER stress引起的未折叠蛋白反应来抵抗细胞凋亡，促进自身生长，但相关机制尚不明确。近期，本项目的研究表明长期ER stress可以导致AsPC-1细胞表达的糖基磷脂酰肌醇锚的朊病毒蛋白（GPI-anchored PrP）转变为原朊病毒蛋白（pro-PrP），从而对ER stress引起的细胞凋亡产生抗性。基于前期工作，本项目提出如下科学假设：长期ER stress改变GPI合成导致pro-PrP的产生，从而抵抗细胞凋亡。为阐明该科学问题，本项目将：（1）揭示长期ER stress导致PDAC细胞生成pro-PrP的分子机制；（2）阐明pro-PrP抵抗ER stress引起的PDAC细胞凋亡的机理。本研究将为PDAC的个性化治疗提供新的靶点和理论依据。

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a lack of early diagnosis and multi-drug resistance. Compared with normal cells sensitive to endoplasmic reticulum (ER) stress, ER stress has been identified in multiple cancers including PDAC, in which unfolded protein response (UPR) induced by ER stress is utilized to inhibit cell apoptosis and to promote cell growth. However, the mechanisms remain incompletely understood. Recently, our study showed that glycosylphosphatidylinositol (GPI)-anchored prion protein (PrP) normally expressed in AsPC-1 cells was converted into as pro-PrP under chronic ER stress, obtaining the capability to resist cell apoptosis. Based on the previous study, our scientific hypothesis is that chronic ER stress results in GPI synthesis changing to produce pro-PrP, so as to protect cells from apoptosis. In order to identify this scientific question, we will reveal the mechanism of chronic ER stress leading to pro-PrP in PDAC cells and pro-PrP promoting resistance of PDAC cells to apoptosis. This study will provide a new target and theory for individualized treatment of PDAC.