Yasuhiro Kazuki
香月 康宏
Department of Chromosome Biomedical Engineering, School of Life Science, Faculty of Medicine, Tottori University/ Chromosome Engineering Research Center, Tottori University
鳥取大学医学部生命科学科染色体医工学講座/ 染色体工学研究センター
染色体工学技術によるヒト化モデル動物の作製と創薬研究への応用
Generation of humanized animal model using chromosome engineering technology and the application for drug discovery
The development of vectors for expressing genes in mammalian cells and animals has not only been a tool for analyzing gene functions, but also has played an important role in industrial and medical applications. Genes that share related functions, or common elements in their regulation, are often clustered in mammalian genomes. These clusters exhibit coordination in the regulation of linked genes and the cis-acting elements responsible for this may be distributed over hundreds of kilobases, or megabase (Mb), distances. In the conventional transgenic technology, the DNA that can be introduced is usually limited to several hundred kb, and it has been impossible to introduce genes or gene clusters having a size exceeding 1 Mb. To solve these problems, we used chromosome engineering technology to develop human artificial chromosomes (HAC) and mouse artificial chromosomes (MAC) that can introduce large human genes, multiple human genes in a stable manner. In this seminar, I will introduce new drug discovery tools (fully human antibody-producing animal containing human Ig locus, mouse/rat expressing human drug metabolism, etc.) developed by HAC/MAC technology, and further introduce new combined technologies of DNA synthesis and HAC/MAC.
References
- Miyamoto H, Kobayashi H, Kishima N, Yamazaki K, Hamamichi S, Uno N, Abe S, Hiramuki Y, Kazuki K, Tomizuka K, Kazuki Y*. Rapid human genomic DNA cloning into mouse artificial chromosome via direct chromosome transfer from human iPSC and CRISPR/Cas9-mediated translocation. Nucleic Acids Res. 2024 Jan 5:gkad1218. doi:10.1093/nar/gkad1218.
- Satofuka H, Abe S, Moriwaki T, Okada A, Kazuki K, Tanaka H, Yamazaki K, Hichiwa G, Morimoto K, Takayama H, Nakayama Y, Hatano S, Yada Y, Murakami Y, Baba Y, Oshimura M, Tomizuka K, and Kazuki Y*. Efficient human-like antibody repertoire and hybridoma production in trans-chromosomic mice carrying megabase-sized human immunoglobulin loci. Nat Commun. 2022 April 5. ;13(1):1841. doi：1038/s41467-022-29421-2.
- Kazuki Y*, Gao FJ, Yamakawa M, Hirabayashi M, Kazuki K, Kajitani N, Miyagawa-Tomita S, Abe S, Sanbo M, Hara H, Kuniishi H, Ichisaka S, Hata Y, Koshima M, Takayama H, Takehara S, Nakayama Y, Hiratsuka M, Iida Y, Matsukura S, Noda N, Li Y, Moyer AJ, Cheng B, Singh N, Richtsmeier JT, Oshimura M, Reeves RH*. A transchromosomic rat model with human chromosome 21 shows robust Down syndrome features. Am J Hum Genet. 2022 Feb 3;109(2):328-344. doi:10.1016/j.ajhg.2021.12.015.
- Moriwaki T, Abe S, Oshimura M, Kazuki Y*. Transchromosomic technology for genomically humanized animals. Exp Cell Res. 2020 May 15;390(2):111914. doi: 10.1016/j.yexcr.2020.111914.
- Kazuki Y*, Kobayashi K, Hirabayashi M, Abe S, Kajitani N, Kazuki K, Takehara S, Takiguchi M, Satoh D, Kuze J, Sakuma T, Kaneko T, Mashimo T, Osamura M, Hashimoto M, Wakatsuki R, Hirashima R, Fujiwara R, Deguchi T, Kurihara A, Tsukazaki Y,Senda N, Yamamoto T, Scheer N, Oshimura M. Humanized UGT2 and CYP3A transchromosomic rats for improved prediction of human drug metabolism. Proc Natl Acad Sci U S A. 2019 Feb 19;116(8):3072-3081. doi: 10.1073/pnas.1808255116.
