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使用多顺反子载体系统生产作为阿尔茨海默病模型的转基因猪。

Production of transgenic pig as an Alzheimer's disease model using a multi-cistronic vector system.

作者信息

Lee Seung-Eun, Hyun Hyuk, Park Mi-Ryung, Choi Youngsok, Son Yeo-Jin, Park Yun-Gwi, Jeong Sang-Gi, Shin Min-Young, Ha Hee-Jin, Hong Hyun-Sok, Choi Min-Keyung, Im Gi-Sun, Park Eung-Woo, Kim Young-Ho, Park Chankyu, Kim Eun-Young, Park Se-Pill

机构信息

Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, Jeju-si, Jeju Special Self-Governing Province, Korea.

Stem Cell Research Center, Jeju National University, Jeju-si, Jeju Special Self-Governing Province, Korea.

出版信息

PLoS One. 2017 Jun 6;12(6):e0177933. doi: 10.1371/journal.pone.0177933. eCollection 2017.

DOI:10.1371/journal.pone.0177933
PMID:28586343
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5460854/
Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with memory loss and cognitive impairments. An AD transgenic (Tg) pig model would be useful for preclinical testing of therapeutic agents. We generated an AD Tg pig by somatic cell nuclear transfer (SCNT) using a multi-cistronic vector that harbored three AD-related genes with a total of six well-characterized mutations: hAPP (K670N/M671L, I716V, and V717I), hTau (P301L), and hPS1 (M146V and L286P). Four AD Tg cell lines were established from Jeju black pig ear fibroblasts (JB-PEFs); the resultant JB-PEFAD cells harbored transgene integration, expressed transgene mRNAs, and had normal karyotypes. Tg line #2-1, which expressed high levels of the transgenes, was used for SCNT; cleavage and blastocyst rates of embryos derived from this line were lower than those of Non-Tg. These embryos yielded three piglets (Jeju National University AD-Tg pigs, JNUPIGs) revealed by microsatellite testing to be genetically identical to JB-PEFAD. Transgenes were expressed in multiple tissues, and at especially high levels in brain, and Aβ-40/42, total Tau, and GFAP levels were high in brains of the Tg animals. Five or more copies of transgenes were inserted into chromosome X. This is the first report of an AD Tg pig derived from a multi-cistronic vector.

摘要

阿尔茨海默病（AD）是一种与记忆丧失和认知障碍相关的进行性神经退行性疾病。AD转基因（Tg）猪模型对于治疗药物的临床前测试将是有用的。我们使用一个多顺反子载体通过体细胞核移植（SCNT）生成了一只AD Tg猪，该载体携带三个与AD相关的基因，共有六个特征明确的突变：hAPP（K670N/M671L、I716V和V717I）、hTau（P301L）和hPS1（M146V和L286P）。从济州黑猪耳部成纤维细胞（JB-PEFs）建立了四个AD Tg细胞系；所得的JB-PEFAD细胞具有转基因整合，表达转基因mRNA，并且具有正常的核型。表达高水平转基因的Tg系#2-1用于SCNT；来自该系的胚胎的卵裂率和囊胚率低于非Tg胚胎。这些胚胎产生了三只仔猪（济州国立大学AD-Tg猪，JNUPIGs），通过微卫星检测显示其与JB-PEFAD基因相同。转基因在多个组织中表达，在脑中表达水平尤其高，并且Tg动物脑中的Aβ-40/42、总Tau和GFAP水平较高。五个或更多拷贝的转基因被插入到X染色体中。这是关于源自多顺反子载体的AD Tg猪的首次报道。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fd5/5460854/c343b9904a17/pone.0177933.g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fd5/5460854/8785ba16584c/pone.0177933.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fd5/5460854/c343b9904a17/pone.0177933.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fd5/5460854/cef619080457/pone.0177933.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fd5/5460854/500777f0507a/pone.0177933.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fd5/5460854/8907f860f94a/pone.0177933.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fd5/5460854/789ca3c9c50b/pone.0177933.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fd5/5460854/53bc45323b02/pone.0177933.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fd5/5460854/8785ba16584c/pone.0177933.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0fd5/5460854/c343b9904a17/pone.0177933.g007.jpg

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