提高哺乳动物工程细胞抗凋亡能力的基因策略

利用哺乳动物细胞发酵生产重组蛋白药物具有细菌、酵母等表达系统所不具备的显著优势,因此在生物制药工程中的重要性越来越突出。哺乳动物细胞对工业生产环境下的各种应激环境耐受能力差,易发生细胞凋亡,严重阻碍了大规模生产,降低了生产效率。细胞凋亡是细胞必经的生物学过程,随着对凋亡机制的深入了解,发展出各种抗凋亡策略,并有望应用于重构更适合工业生产的工程细胞。常用的抗凋亡策略包括:下调凋亡蛋白、上调抗凋亡蛋白、增强生长因子自表达、减少有毒代谢产物生成等。以上策略虽然能在一定程度上提高细胞的抗凋亡能力,但距离满足生产的工程细胞重构还有距离,围绕提高工程细胞的抗凋亡能力,已发展出"凋亡工程"这一重要的技术领域。

Gene Strategies of Enhancing the Anti-apoptosis Ability of Mammalian Cell in Engineering

Mammalian cells have significant advantages in producing recombinant protein drugs,which make it widely used in industry.In the process of production,however,environmental stress,which can result from nutrient depletion and by-product accumulation,activates apoptosis through signalling cascades regulators.It is the burden of improving the protein production that have the cell more susceptible to apoptosis,decreasing bioreactor performance and hindering large-scale production.Therefore,apoptosis,programed cell death,seriously limits the recombinant protein production,and how to improve the anti-apoptotic ability of engineering cells has accordingly become a hot point that attracted the attention of biologists all over the world.Apoptosis,as well as proliferation and differentiation,is one of the biological processes that cell must experience.With the understanding of the mechanism of apoptosis and revealing of many apoptosis genes in previous studies,a variety of anti-apoptotic approaches were found which is helpful to inhibit apoptosis and to enhance the robustness,survival and productivity of production cell lines.The anti-apoptotic approaches commonly used in engineering include: lowering apoptotic proteins,increasing anti-apoptotic proteins,over-expressing growth factor and insuin-like growth factor and modifying the intracellular enzyme related to metabolism in order to prevent the toxic metabolites from accumulating.Although the resistance of cell to apoptosis were,to some extent,improved by the strategies mentioned above,it is very essential for biotechnologists to search for more effective anti-apoptotic approaches that could lead to the greatest improvements in cell survival,provide unequalled bioreactor performance and enhance biopharmaceutical productivities.