期刊
GASTROENTEROLOGY
卷 155, 期 6, 页码 1967-+出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2018.08.037
关键词
Liver Gene Knockout; SLiK; CRISPR/Cas9; Mouse Models
资金
- National Heart, Lung, and Blood Institute (NHLBI) [R01HL134510]
- National Institute of Diabetes and Digestive and Kidney Disease [R56DK115461, R01DK115461]
- Texas Hepatocellular Carcinoma Consortium [RP150587]
- NHLBI [HL132840]
- National Cancer Institute [NCI] [P30CA125123]
- National Institute of Diabetes and Digestive and Kidney Disease [NIDDK] [P30-DK56338]
- National Heart, Lung, and Blood Institute [NHLBI] [T32HL092332]
- Diana Helis Henry Medical Research Foundation
- Adrienne Helis Malvin Medical Research Foundation
- NATIONAL CANCER INSTITUTE [P30CA125123] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL132840, R01HL134510, T32HL092332] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R56DK115461, P30DK056338, R01DK115461] Funding Source: NIH RePORTER
BACKGROUND & AIMS: Despite advances in gene editing technologies, generation of tissue-specific knockout mice is time-consuming. We used CRISPR/Cas9-mediated genome editing to disrupt genes in livers of adult mice in just a few months, which we refer to as somatic liver knockouts. METHODS: In this system, Fah(-/-) mice are given hydrodynamic tail vein injections of plasmids carrying CRISPR/Cas9 designed to excise exons in Hpd; the Hpd-edited hepatocytes have a survival advantage in these mice. Plasmids that target Hpd and a separate gene of interest can therefore be used to rapidly generate mice with liver-specific deletion of nearly any gene product. RESULTS: We used this system to create mice with liver-specific knockout of argininosuccinate lyase, which develop hyperammonemia, observed in humans with mutations in this gene. We also created mice with liver-specific knockout of ATP binding cassette subfamily B member 11, which encodes the bile salt export pump. We found that these mice have a biochemical phenotype similar to that of Abcb11(-/-) mice. We then used this system to knock out expression of 5 different enzymes involved in drug metabolism within the same mouse. CONCLUSIONS: This approach might be used to develop new models of liver diseases and study liver functions of genes that are required during development.
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