基因组缺陷与多种脑内疾病有关，改造缺陷基因可从根本上阻断疾病进程。目前尚无有效的方法实现脑基因组原位编辑。以多肽为载体，引导转录激活因子样效应物核酸酶(TALEN)靶脑转运是解决这个难题的有效途径。本项目使用靶脑功能的RDP多肽，以Huntington's综合征致病关键基因it-15为对象，从三个方面阐明TALEN进入神经细胞定点修改靶基因：(1)构建在神经细胞发挥作用的TALEN质粒并制备RDP-TALEN蛋白，通过细胞和小鼠体内实验验证RDP-TALEN进入脑细胞对基因组编辑并影响Huntington's综合征进程；(2)RDP与包含特异启动子的TALEN质粒形成多肽/核酸复合物，验证TALEN仅在脑多巴胺神经元表达并起作用；(3)探讨多肽携带TALEN蛋白及核酸的穿膜机制。本研究可为体内人工编辑脑细胞基因组提供安全有效的方法、并为探索神经元基因与动物疾病之间的关系，提供重要的理论依据。

Gene deficiency are always related to brain disorders, and naturally, the optimal approach of preventing disease progress is to modify and correct the defective gene. Until now, there is no effective method to achieve brain genome editing in situ. To address this problem, we propose a brain-targeting delivery carrier, RDP peptide, to conjugate with transcription activator-like effector nucleases (TALEN), a macromolecule for genome editing, and to deliver TALEN across the blood-brain barrier and into neuronal cells. In this study, we will demonstrate the biological avitivities of the conjugation of RDP and TALEN in three aspects, by using the TALENs knockout the key gene of Huntington's disease, it-15 (Htt): (1) the gene vector of TALEN in neuronal cells is constructed, the fusion protein of RDP-TALEN is prepared through gene engineering technology, and both cell culture and animal studies will be used to determine that the interest gene can be knocked out, then the progress of experimental Huntington's disease may be prevented when RDP-TALEN is delivered into mouse brain cells; (2) only in dopaminergic neuron of brain, TALEN gene will be expressed and play roles when the mice are administrated RDP/DNA complex, which is produced by RDP linked with TALEN gene containing specific promoter; (3) the transport mechanism of RDP-TALEN fusion protein and peptide/DNA complex will be investigated. The finding of this study will provide a safe and effective approach to edit artificially brain genome in vivo, and will supply important information and new knowledge essential for investigating the relationship between neuronal cell gene and animal diseases in theoretical framework and technical support.