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Generation of obese rat model by transcription activator-like effector nucleases targeting the leptin receptor gene

Science China(Life Sciences) 2017年第2期60卷 152-157页

作者： Yuting Chen Wenqing Lu Na Gao Yi Long Yanjiao Shao Meizhen Liu Huaqing Chen Shixin Ye Xueyun Ma Mingyao Liu Dali Li Shanghai Key Laboratory of Regulatory Biology Institute of Biomedical Sciences and School of Life Sciences East China Normal University Shanghai 200241 China Ecole Normale Supérieure Institut de Biologie de l' Ecole Normale Supérieure Institut National de la Santé et de la Recherche Médicale U1024 Centre National de la Recherche Scientifique Unité Mixte de Recherche 8197 Paris F-75005 France Institute of Biosciences and Technology Department of Molecular and Cellular Medicine Texas A&M University Health Science Center Houston Texas 77030 USA

The laboratory rat is a valuable mammalian model organism for basic research and drug discovery. Here we demonstrate an efficient methodology by applying transcription activator-like effector nucleases(TALENs) technology to generate Leptin receptor(Lepr) knockout rats on the Sprague Dawley(SD) genetic background. Through direct injection of in vitro transcribed m RNA of TALEN pairs into SD rat zygotes, somatic mutations were induced in two of three resulting pups. One of the founders carrying bi-allelic mutation exhibited early onset of obesity and infertility. The other founder carried a chimeric mutation which was efficiently transmitted to the progenies. Through phenotyping of the resulting three lines of rats bearing distinct mutations in the Lepr locus, we found that the strains with a frame-shifted or premature stop codon mutation led to obesity and metabolic disorders. However, no obvious defect was observed in a strain with an in-frame 57 bp deletion in the extracellular domain of Lepr. This suggests the deleted amino acids do not significantly affect Lepr structure and function. This is the first report of generating the Lepr mutant obese rat model in SD strain through a reverse genetic approach. This suggests that TALEN is an efficient and powerful gene editing technology for the generation of disease models.

关键词： TALENs Lepr knockout rat germ-line transmission

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Retake the Center Stage-New Development of rat Genetics

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Journal of Genetics and Genomics 2012年第6期39卷 261-268页

作者： Sushuang Zheng Kindiya Geghman Sushila Shenoy Chenjian Li Departntent of Neunrology. Friedman Brain Institute Mt. Sinai School of Medicine Box 1137 New York NY 10029 USA College of Life Sciences Peking Univetsitv Beijing 100871 China

The rat is a powerful model for the study of human physiology and diseases, and is prefened by physiologists, neuroscientists and toxicologists. However, the lack of robust genetic modification tools has severely limited the generation of rat genetic models over the last two decades. In the last few years, several gene-targeting strategies have been developed in rats using N-ethyl-N-nitrosourea （ENU）, transposons, zinc-finger nucleases （ZFNs）, bacterial a11ificial chromosome （BAC） mediated transgenesis, and recently established rat embryonic stem （ES） cells. The development and improvement of these approaches to genetic manipulation have created a bright future lbr the use of genetic rat models in investigations of gene function and human diseases. Here, we summarize the strategies used for rat genetic manipulation in current research. We also discuss BAC transgenesis as a potential tool in rat transgenic models.

关键词： rat model BAC knockout rat Transgenic rat Mutagenesis

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Npy deletion in an alcohol non-preferring rat model elicits differential effects on alcohol consumption and body weight

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Journal of Genetics and Genomics 2016年第7期43卷 421-430页

作者： Bin Qiu Richard L.Bell Yong Cao Lingling Zhang Robert B.Stewart Tamara Graves Lawrence Lumeng Weidong Yong Tiebing Liang Institute of Laboratory Animal Science Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100021 China Department of Psychiatry Indiana University School of Medicine Indianapolis IN 46202 USA Department of Gastroenterology Indiana University School of Medicine Indianapolis IN 46202 USA Department of Psychology Purdue School of Science Indiana University-Purdue University of Indianapolis Indianapolis IN 46202 USA Experimental Medicine Center The First Affiliated Hospital of Sichuan Medical University Luzhou 646000 China

Neuropeptide Y（NPY） is widely expressed in the central nervous system and influences many physiological *** is located within the rat quantitative trait locus（QTL） for alcohol preference on chromosome ***-nonpreferring（NP） rats consume very little alcohol,but have significantly higher NPY expression in the brain than alcohol-preferring（P） *** capitalized on this phenotypic difference by creating an Npy knockout（KO） rat using the inbred NP background to evaluate NPY effects on alcohol *** finger nuclease（ZNF） technology was applied,resulting in a 26-bp deletion in the Npy ***-PCR,Western blotting and immunohistochemistry confirmed the absence of Npy mRNA and protein in KO *** consumption was increased in Npy＋/- but not Npy-/- rats,while Npy-/- rats displayed significantly lower body weight when compared to Npy^（＋/＋） *** whole brain tissue,expression levels of Npy-related and other alcohol-associated genes,Npy1 r,Npy2r,Npy5 r,Agrp,Mc3 r,Mc4r,Crh and CrMr,were significantly greater in Npy-/- rats,whereas Pome and Crhr2 expressions were highest in Npy＋/- *** findings suggest that the NPY-system works in close coordination with the melanocortin（MC） and corticotropin-releasing hormone（CRH） systems to modulate alcohol intake and body weight.

关键词： knockout rat Alcohol drinking behavior NPY and receptors CRH and receptors Melanocortin and receptors BDNF

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TRDMT1 exhibited protective effects against LPS-induced inflammation in rats through TLR4-NF-κB/MAPK-TNF-αpathway

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Animal Models and Experimental Medicine 2022年第2期5卷 172-182页

作者： Zhengguang Li Xiaolong Qi Xu Zhang Lei Yu Lijuan Gao Weining Kong Wei Chen Wei Dong Lijun Luo Dan Lu Lianfeng Zhang Yuanwu Ma Key Laboratory of Human Disease Comparative Medicine National Health Commission of China(NHC)Institute of Laboratory Animal ScienceChinese Academy of Medical SciencesPeking Union Medicine CollegeBeijingChina National Human Diseases Animal Model Resource Center and Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases Institute of Laboratory Animal SciencePeking Union Medicine CollegeChinese Academy of Medical SciencesBeijingChina Neuroscience Center Chinese Academy of Medical SciencesBeijingChina

Background:Inflammation is a complex physiological and pathological *** many types of inflammation are well characterized,their physiological func-tions are largely *** aspartic acid methyltransferase 1(TRDMT1)has been implicated as a stress-related protein,but its intrinsic biological role is ***:We constructed a Trdmt1 knockout rat and adopted the LPS-induced sepsis *** curve,histopathological examination,expression of inflammatory fac-tors,and protein level of TLR4 pathway were ***:Trdmt1 deletion had no obvious impact on development and ***1 de-letion slightly increased the mortality during *** data showed that Trdmt1 strongly responded in LPS-treated rats,and Trdmt1 knockout rats were vulnerable to LPS treat-ment with declined survival *** also observed more aggravated tissue damage and more cumulative functional cell degeneration in LPS-treated knockout rats compared with control *** studies showed upregulated TNF-αlevel in liver,spleen,lung,and serum tissues,which may be explained by enhanced p65 and p38 ***:Our data demonstrated that Trdmt1 plays a protective role in inflamma-tion by regulating the TLR4-NF-κB/MAPK-TNF-α*** work provides useful information to understand the TRDMT1 function in inflammation.

关键词： inflammation knockout rat TLR4 pathway TNF-α Trdmt1

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