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学科主题基础医学
An Over Expression APP Model for Anti-Alzheimer Disease Drug Screening Created by Zinc Finger Nuclease Technology
Zhang, Xiaojing1; Li, Hui1; Mao, Yiqing1; Li, Zhixin1; Wang, Rong1; Guo, Tingting1; Jin, Ling1; Song, Rongjing1; Xu, Wei1; Zhou, Na1; Zhang, Yizhuang1; Hu, Ruobi1; Wang, Xi1; Huang, Huakang1; Lei, Zhen4; Niu, Gang3; Irwin, David M.1,2; Tan, Huanran1
刊名PLOS ONE
2013-11-06
DOI10.1371/journal.pone.0075493
8期:11
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Multidisciplinary Sciences
资助者National Natural Science Foundation of China (NSFC) ; National Key Technologies RD Program ; National Science Foundation of China - Canadian Institutes of Health Research (NSFC-CIHR) China-Canada Joint Health Research Initiative ; National Natural Science Foundation of China (NSFC) ; National Key Technologies RD Program ; National Science Foundation of China - Canadian Institutes of Health Research (NSFC-CIHR) China-Canada Joint Health Research Initiative
研究领域[WOS]Science & Technology - Other Topics
关键词[WOS]AMYLOID-BETA PEPTIDE ; HOMOLOGOUS RECOMBINATION ; GAMMA-SECRETASE ; KNOCKOUT RATS ; CELLS ; PROTEIN ; DNA ; CYCLOOXYGENASE ; HYPOTHESIS ; INHIBITORS
英文摘要

Zinc Finger Nucleases (ZFNs), famous for their ability to precisely and efficiently modify specific genomic loci, have been employed in numerous transgenic model organism and cell constructions. Here we employ the ZFNs technology, with homologous recombination (HR), to construct sequence-specific Amyloid Precursor Protein (APP) knock-in cells. With the use of ZFNs, we established APP knock in cell lines with gene-modification efficiencies of about 7%. We electroporated DNA fragment containing the promoter and the protein coding regions of the zinc finger nucleases into cells, instead of the plasmids, to avoid problems associated with off target homologous recombination, and adopted a pair of mutated FokI cleavage domains to reduce the toxic effects of the ZFNs on cell growth. Since over-expression of APP, or a subdomain of it, might lead to an immediately lethal effect, we used the Cre-LoxP System to regulate APP expression. Our genetically transformed cell lines, w5c1 and s12c8, showed detectable APP and Amyloid beta (A beta) production. The Swedish double mutation in the APP coding sequence enhanced APP and A beta abundance. What is more, the activity of the three key secretases in A beta formation could be modulated, indicating that these transgenic cells have potential for drug screening to modify amyloid metabolism in cells. Our transformed cells could readily be propagated in culture and should provide an excellent experimental medium for elucidating aspects of the molecular pathogenesis of Alzheimer′s disease, especially those concerning the amyloidogenic pathways involving mutations in the APP coding sequence. The cellular models may also serve as a tool for deriving potentially useful therapeutic agents.

语种英语
所属项目编号30772603 ; 2006BAF07B01 ; 2009BAK61B01 ; 2009BAK61B04?2012BAK25B01 ; 81061120525 ; CCI-109605
资助者National Natural Science Foundation of China (NSFC) ; National Key Technologies RD Program ; National Science Foundation of China - Canadian Institutes of Health Research (NSFC-CIHR) China-Canada Joint Health Research Initiative ; National Natural Science Foundation of China (NSFC) ; National Key Technologies RD Program ; National Science Foundation of China - Canadian Institutes of Health Research (NSFC-CIHR) China-Canada Joint Health Research Initiative
WOS记录号WOS:000326656200006
引用统计
被引频次:2[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/57168
专题基础医学院_药理学系
作者单位1.Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada
2.Beijing N&N Genetech Co, Beijing, Peoples R China
3.Ningxia Med Univ, Dept Pharmacol, Yinchuan, Peoples R China
4.Peking Univ, Hlth Sci Ctr, Dept Pharmacol, Beijing 100871, Peoples R China
推荐引用方式
GB/T 7714
Zhang, Xiaojing,Li, Hui,Mao, Yiqing,et al. An Over Expression APP Model for Anti-Alzheimer Disease Drug Screening Created by Zinc Finger Nuclease Technology[J]. PLOS ONE,2013,8(11).
APA Zhang, Xiaojing.,Li, Hui.,Mao, Yiqing.,Li, Zhixin.,Wang, Rong.,...&Tan, Huanran.(2013).An Over Expression APP Model for Anti-Alzheimer Disease Drug Screening Created by Zinc Finger Nuclease Technology.PLOS ONE,8(11).
MLA Zhang, Xiaojing,et al."An Over Expression APP Model for Anti-Alzheimer Disease Drug Screening Created by Zinc Finger Nuclease Technology".PLOS ONE 8.11(2013).
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