Development of novel gene delivery systems based on the function of biological molecules

在本研究项目中，我们研究了生物系统的基本功能，如病毒和染色体，这将有助于开发新的非病毒基因转移和表达装置。我们在这个项目期间所取得的成果总结如下。我们分析了膜融合介导高效DNA传递的机制，发现膜融合需要一些非受体分子，这些非受体分子可能与仙台病毒HN蛋白相互作用。我们建立了在λ噬菌体颗粒表面展示各种生物多肽的系统，并提出利用该系统分析这些多肽作为非病毒基因传递载体的功能。利用该系统，我们发现Tat肽可以增强λ噬菌体DNA向细胞内的传递，并且SV40 T抗原的NLS信号肽可以通过核孔复合物将λ噬菌体颗粒靶向进入细胞核。我们分析了人类染色体在细胞核内稳定的机制，发现TRF1和端粒重复序列之间的相互作用参与了这一过程。我们成功地用包裹癌症特异性自杀基因的融合性脂质体治疗了患有播散性癌症的小鼠。

In this research project, we investigate the essential function of biological systems, such as viruses and chromosomes, which will be useful for developing novel non-viral devices for gene transfer and expression. The results we have obtained during the term of this project are summarized as below.1. We analyzed the mechanism of membrane fusion that will mediated efficient DNA delivery, and found that the membrane fusion requires essential non-receptor molecules which may be interacted with HN protein of Sendai virus.2. We establish the system to display various biological peptides on the surface of lambda phage particles, and propose to use this system to analyze the function of these peptides as components of non-viral gene delivery vehicles. Using this system, we showed that Tat peptide could enhance the delivery of lambda phage DNA into the cells and that NLS signal peptide of SV40 T antigen could target the lambda phage particles into the nucleus through the nuclear pore complex.3. We analyze the mechanism by which human chromosomes are stabilized in the nucleus, and found that the interaction between TRF1 and telomere repeat was involved in this process.4. We succeeded to cure mice with the disseminated cancer by treating them with the fusogenic liposomes encapsulating cancer-specific suicide gene.