朊病毒病(Prion disease）的病因为体内正常的朊蛋白(PrPC)发生构象改变形成异常朊病毒(PrPSc)所致。朊蛋白的α切割被认为是在发病过程中对机体起着保护作用。TACE为α切割主要内切酶之一，PDK1是影响着TACE活性的重要因子。抑制PDK1活性能够提高TACE活性，从而延长实验动物生命。MiRNAs是一种体内调节蛋白表达的保守小分子。MiR-375能够调控PDK1的表达及活性。因此，我们推测MiR-375很可能通过调控TACE从而调控着PrPSc的形成。本研究拟以细胞/动物中的miR-375对PDK1/TACE活性和PrPSc形成的影响进行研究，同时以建立的小鼠感染脑组织中与PrPC α-内切酶相关的miRNA时间的变化谱，分析并寻找靶标蛋白/miRNA，研究其在朊病毒感染过程中的机制，并为寻找潜在的朊病毒病诊断及治疗靶标提供科学依据和线索。

Prion disease was caused by a pathological protein prion which was misfolded by a normal cellular isoform. Prion α-cleavages was consider as a protective factor in prion disease. TACE (tumor necrosis factor-α-converting enzyme) was one of the PrP α-secretases whose activity was regulated by PDK1 (3-phosphoinositide-dependent kinase-1). Survival time was increased when TACE activity was increased by PDK1 inhibitor in animal experiment. miRNAs are small non-coding RNA molecules, which function in transcriptional and post-transcriptional regulation of gene expression. MiR-375 was a regulator of PDK1. Therefore, we speculate that formation of PrPSc can be effected by miR-375 through PDK1/TACE way. In this project, cell lines and brain of prion-infected mouse will be used to detect the miR-375 and PDK1/TACE during disease progression.Their functions on the fomation of PrPSc were also evaluated. More miRNAs, which were changed in disease progression, involved in PrPC α-cleavages were also focused on. These research work will not only make us better understand the pathogenesis of prion disease, but also provide clues for diagnosis and treatment of this disease.