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Crispr/cas9 hepatitis

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https://www.readbyqxmd.com/read/29343656/crispr-cas9-mediated-generation-of-obese-and-diabetic-mouse-models
#1
Jae-Il Roh, Junghoon Lee, Seong Uk Park, Young-Shin Kang, Jaehoon Lee, Ah-Reum Oh, Dong Joon Choi, Ji-Young Cha, Han-Woong Lee
Mouse models of obesity (ob/ob) and diabetes (db/db) in which the leptin (Lep) and Leptin receptor (Lepr) genes have been mutated, respectively, have contributed to a better understanding of human obesity and type 2 diabetes and to the prevention, diagnosis, and treatment of these metabolic diseases. In this study, we report the first CRISPR-Cas9-induced Lep and Lepr KO mouse models by co-microinjection of Cas9 mRNA and sgRNAs that specifically targeted Lep or Lepr in C57BL/6J embryos. Our newly established Lep and Lepr knockout (KO) mouse models showed phenotypic disorders nearly identical to those found in ob/ob and db/db mice, such as an increase in body weight, hyperglycemia, and hepatic steatosis...
January 16, 2018: Experimental Animals
https://www.readbyqxmd.com/read/29289533/ldl-receptor-gene-ablated-hamsters-a-rodent-model-of-familial-hypercholesterolemia-with-dominant-inheritance-and-diet-induced-coronary-atherosclerosis
#2
Xin Guo, Mingming Gao, Yunan Wang, Xiao Lin, Liu Yang, Nathan Cong, Xiangbo An, Feng Wang, Kai Qu, Liqing Yu, Yuhui Wang, Jinjie Wang, Haibo Zhu, Xunde Xian, George Liu
Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease caused mainly by LDL receptor (Ldlr) gene mutations. Unlike FH patients, heterozygous Ldlr knockout (KO) mice do not show a dominant FH trait. Hamsters, like humans, have the cholesteryl ester transfer protein, intestine-only ApoB editing and low hepatic cholesterol synthesis. Here, we generated Ldlr-ablated hamsters using CRISPR/Cas9 technology. Homozygous Ldlr KO hamsters on a chow diet developed hypercholesterolemia with LDL as the dominant lipoprotein and spontaneous atherosclerosis...
December 15, 2017: EBioMedicine
https://www.readbyqxmd.com/read/29277559/pan-genotype-hepatitis-e-virus-replication-in-stem-cell-derived-hepatocellular-systems
#3
Xianfang Wu, Viet Loan Dao Thi, Peng Liu, Constantin N Takacs, Kuanhui Xiang, Linda Andrus, Jérôme Gouttenoire, Darius Moradpour, Charles M Rice
BACKGROUND & AIMS: The 4 genotypes of hepatitis E virus (HEV) that infect humans (genotypes 1-4) vary in geographical distribution, transmission, and pathogenesis. Little is known about the properties of HEV or its hosts that contribute to these variations. Primary isolates grow poorly in cell culture; most studies have relied on variants adapted to cancer cell lines, which likely alter virus biology. We investigated the infection and replication of primary isolates of HEV in hepatocyte-like cells (HLCs) derived from human embryonic and induced pluripotent stem cells...
December 22, 2017: Gastroenterology
https://www.readbyqxmd.com/read/29259521/nuclease-mediated-gene-therapies-for-inherited-metabolic-diseases-of-the-liver%C3%A2-%C3%A2
#4
REVIEW
Taylor E Bryson, Caitlin M Anglin, P Hudson Bridges, Renee N Cottle
Inherited metabolic diseases (IMDs) of the liver represent a vast and diverse group of rare genetic diseases characterized by the loss or dysfunction of enzymes or proteins essential for metabolic pathways in the liver. Conventional gene therapy involving adeno-associated virus (AAV) serotype 8 vectors provide therapeutically high levels of hepatic transgene expression facilitating the correction of the disease phenotype in pre-clinical studies and are currently being evaluated in clinical trials for multiple IMDs...
December 2017: Yale Journal of Biology and Medicine
https://www.readbyqxmd.com/read/29207996/crispr-cas9-mediated-gene-deletions-in-lager-yeast-saccharomyces-pastorianus
#5
Arthur R Gorter de Vries, Philip A de Groot, Marcel van den Broek, Jean-Marc G Daran
BACKGROUND: The ease of use of CRISPR-Cas9 reprogramming, its high efficacy, and its multiplexing capabilities have brought this technology at the forefront of genome editing techniques. Saccharomyces pastorianus is an aneuploid interspecific hybrid of Saccharomyces cerevisiae and Saccharomyces eubayanus that has been domesticated for centuries and is used for the industrial fermentation of lager beer. For yet uncharacterised reasons, this hybrid yeast is far more resilient to genetic alteration than its ancestor S...
December 5, 2017: Microbial Cell Factories
https://www.readbyqxmd.com/read/29207074/establishment-of-a-novel-hepatic-steatosis-cell-model-by-cas9-sgrna-mediated-dgk%C3%AE-gene-knockout
#6
Jingjing Zhang, Junli Zhao, Xiaojing Zheng, Kai Cai, Qinwen Mao, Haibin Xia
To investigate the role of diacylglycerol kinase θ (DGKθ) in lipid metabolism and insulin resistance, the present study generated an in vitro hepatic steatosis cell model by knockout of the DGKθ gene in liver cancer cell line HepG2 using CRISPR/Cas9 technology. The cell line was characterized by Oil Red O staining and shown to exhibit increased intracellular lipid accumulation, compared with that in wild‑type liver cancer cell line HepG2. The gene expression levels of signaling proteins in pathways involved in lipid metabolism, insulin resistance and gluconeogenesis were also examined...
November 22, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29097363/interrogation-of-the-atherosclerosis-associated-sort1-sortilin-1-locus-with-primary-human-hepatocytes-induced-pluripotent-stem-cell-hepatocytes-and-locus-humanized-mice
#7
Xiao Wang, Avanthi Raghavan, Derek T Peters, Evanthia E Pashos, Daniel J Rader, Kiran Musunuru
OBJECTIVE: The noncoding single-nucleotide polymorphism rs12740374 has been hypothesized to be the causal variant responsible for liver-specific modulation of SORT1(sortilin 1) expression (ie, expression quantitative trait locus) and, by extension, the association of the SORT1 locus on human chromosome 1p13 with low-density lipoprotein cholesterol levels and coronary heart disease. The goals of this study were to compare 3 different hepatocyte models in demonstrating that the rs12740374 minor allele sequence is responsible for transcriptional activation of SORT1 expression...
November 2, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/29091957/hepatitis-e-virus-hev-egress-role-of-bst2-tetherin-and-interferon-induced-long-non-coding-rna-lncrna-bispr
#8
Daizy Paliwal, Prashant Joshi, Subrat Kumar Panda
BACKGROUND: The biology of Hepatitis E Virus (HEV), a common cause of epidemic and sporadic hepatitis, is still being explored. HEV exits liver through bile, a process which is essential for its natural transmission by feco-oral route. Though the process of this polarised HEV egress is not known in detail, HEV pORF3 and hepatocyte actin cytoskeleton have been shown to play a role. METHODS: Our transcriptome analysis in Hepatitis E virus (HEV) replicon transfected Huh7 cells at 24 and 72 hrs indicated that at 24hrs, both LncBISPR and BST2, expressed by a bidirectional promoter were highly upregulated whereas at 72 hrs, BST2 expression was comparatively reduced accompanied by normal levels of BISPR...
2017: PloS One
https://www.readbyqxmd.com/read/29034887/generation-of-three-mir-122-knockout-lines-from-a-human-embryonic-stem-cell-line
#9
Yanli Liu, Feima Wu, Yuanqi Zhuang, Dongsheng Guo, Nasir Abbas, Ruzi Wei, Kepin Wang, Yan Chen, Jiawang Tao, Yuhang Wu, Fang Yuan, Tingcai Pan, Fan Yang, Keyu Lai, Liangxue Lai, Yin-Xiong Li
miR-122 is the most abundant miRNA in the human liver, accounting for 52% of the entire hepatic miRNome. Previous studies have demonstrated that miR-122 plays key roles in hepatocyte growth, metabolism, and homeostasis. Here, we created three miR-122 knockout human embryonic stem cell line lines, WAe001-A-7, WAe001-A-8, and WAe001-A-9, using the CRISPR/Cas9 technique. These mutated cell lines retained their pluripotency, in vitro differentiation potential, normal morphology, and karyotype.
October 2017: Stem Cell Research
https://www.readbyqxmd.com/read/29029439/microrna-149-suppresses-hepatic-inflammatory-response-through-antagonizing-stat3-signaling-pathway
#10
Qiqi Zhang, Jia Su, Ziwei Wang, Hui Qi, Zeyong Ge, Zhijun Li, Wei-Dong Chen, Yan-Dong Wang
Chronic inflammation is increasingly recognized as an important component of tumorigenesis and metabolic diseases. The roles of microRNA149* (miRNA149*) in inflammation remain poorly understood. Here, we demonstrate that miR-149* is a suppressor of STAT3-mediated inflammation. MiR-149*(-/-) mice were generated with CRISPR/CAS9 technique. In a lipopolysaccharide (LPS)-induced inflammation model, miR-149*(-/-) mice show more severe liver injury and inflammation, compared with wild-type (WT) mice. MiR-149*(-/-) mice also displayed elevated messenger RNA (mRNA) levels of interleukin (IL)-6, inducible nitric oxide synthase (iNOS), complement C3 (C3) and IL-4 in response to LPS...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/28956740/genetic-correction-and-hepatic-differentiation-of-hemophilia-b-specific-human-induced-pluripotent-stem-cells
#11
Qiong He, Hui-Hui Wang, Tao Cheng, Wei-Ping Yuan, Yu-Po Ma, Yong-Ping Jiang, Zhi-Hua Ren
Objective To genetically correct a disease-causing point mutation in human induced pluripotent stem cells (iPSCs) derived from a hemophilia B patient. Methods First, the disease-causing mutation was detected by sequencing the encoding area of human coagulation factor IX (F IX) gene. Genomic DNA was extracted from the iPSCs, and the primers were designed to amplify the eight exons of F IX. Next, the point mutation in those iPSCs was genetically corrected using CRISPR/Cas9 technology in the presence of a 129-nucleotide homologous repair template that contained two synonymous mutations...
September 27, 2017: Chinese Medical Sciences Journal, Chung-kuo i Hsüeh K'o Hsüeh Tsa Chih
https://www.readbyqxmd.com/read/28944845/efficient-inhibition-of-duck-hepatitis-b-virus-dna-by-the-crispr-cas9-system
#12
Qingfen Zheng, Li Bai, Sujun Zheng, Mei Liu, Jinyan Zhang, Ting Wang, Zhongwei Xu, Yu Chen, Jiansheng Li, Zhongping Duan
Current therapeutic strategies cannot eradicate hepatitis B virus covalently closed circular DNA (HBV cccDNA), which accounts for the persistence of HBV infection. Very recently, the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR‑associated protein 9 (Cas9) system has been used as an efficient and powerful tool for viral genome editing. Given that the primary duck hepatocyte (PDH) infected with duck hepatitis B virus (DHBV) has been widely used to study human HBV infection in vitro, the present study aimed to demonstrate the targeted inhibition of DHBV DNA, especially cccDNA, by the CRISPR/Cas9 system using this model...
November 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28939663/hepatoma-intrinsic-ccrk-inhibition-diminishes-myeloid-derived-suppressor-cell-immunosuppression-and-enhances-immune-checkpoint-blockade-efficacy
#13
Jingying Zhou, Man Liu, Hanyong Sun, Yu Feng, Liangliang Xu, Anthony W H Chan, Joanna H Tong, John Wong, Charing Ching Ning Chong, Paul B S Lai, Hector Kwong-Sang Wang, Shun-Wa Tsang, Tyler Goodwin, Rihe Liu, Leaf Huang, Zhiwei Chen, Joseph Jy Sung, King Lau Chow, Ka Fai To, Alfred Sze-Lok Cheng
OBJECTIVE: Myeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC). DESIGN: Immunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems...
September 22, 2017: Gut
https://www.readbyqxmd.com/read/28874468/tim1-havcr1-is-not-essential-for-cellular-entry-of-either-quasi-enveloped-or-naked-hepatitis-a-virions
#14
Anshuman Das, Asuka Hirai-Yuki, Olga González-López, Bethany Rhein, Sven Moller-Tank, Rachel Brouillette, Lucinda Hensley, Ichiro Misumi, William Lovell, John M Cullen, Jason K Whitmire, Wendy Maury, Stanley M Lemon
Receptor molecules play key roles in the cellular entry of picornaviruses, and TIM1 (HAVCR1) is widely accepted to be the receptor for hepatitis A virus (HAV), an unusual, hepatotropic human picornavirus. However, its identification as the hepatovirus receptor predated the discovery that hepatoviruses undergo nonlytic release from infected cells as membrane-cloaked, quasi-enveloped HAV (eHAV) virions that enter cells via a pathway distinct from naked, nonenveloped virions. We thus revisited the role of TIM1 in hepatovirus entry, examining both adherence and infection/replication in cells with clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-engineered TIM1 knockout...
September 5, 2017: MBio
https://www.readbyqxmd.com/read/28859855/degradation-of-phlpp2-by-kctd17-via-a-glucagon-dependent-pathway-promotes-hepatic-steatosis
#15
KyeongJin Kim, Dongryeol Ryu, Paola Dongiovanni, Lale Ozcan, Shruti Nayak, Beatrix Ueberheide, Luca Valenti, Johan Auwerx, Utpal B Pajvani
BACKGROUND & AIMS: Obesity-induced non-alcoholic fatty liver disease (NAFLD) develops, in part, via excess insulin-stimulated hepatic de novo lipogenesis, which increases, paradoxically, in patients with obesity-induced insulin resistance. Pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) terminates insulin signaling by dephosphorylating Akt; levels of PHLPP2 are reduced in livers from obese mice. We investigated whether loss of hepatic PHLPP2 is sufficient to induce fatty liver in mice, mechanisms of PHLPP2 degradation in fatty liver, and expression of genes that regulate PHLPP2 in livers of patients with NAFLD...
August 28, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28839466/the-grna-mirna-grna-ternary-cassette-combining-crispr-cas9-with-rnai-approach-strongly-inhibits-hepatitis-b-virus-replication
#16
Jie Wang, Ran Chen, Ruiyang Zhang, Shanlong Ding, Tianying Zhang, Quan Yuan, Guiwen Guan, Xiangmei Chen, Ting Zhang, Hui Zhuang, Frederick Nunes, Timothy Block, Shuang Liu, Zhongping Duan, Ningshao Xia, Zhongwei Xu, Fengmin Lu
The CRISPR/Cas9 system is a novel genome editing technology which has been successfully used to inhibit HBV replication. Here, we described a novel gRNA-microRNA (miRNA)-gRNA ternary cassette driven by a single U6 promoter. With an anti-HBV pri-miR31 mimic integrated between two HBV-specific gRNAs, both gRNAs could be separated from the long transcript of gRNA-miR-HBV-gRNA ternary cassette through Drosha/DGCR8 processing. The results showed that the gRNA-miR-HBV-gRNA ternary cassette could efficiently express two gRNAs and miR-HBV...
2017: Theranostics
https://www.readbyqxmd.com/read/28636533/microrna-149-suppresses-hepatic-inflammatory-response-through-antagonizing-stat3-signaling-pathway
#17
Qiqi Zhang, Jia Su, Ziwei Wang, Hui Qi, Zeyong Ge, Zhijun Li, Wei-Dong Chen, Yan-Dong Wang
Chronic inflammation is increasingly recognized as an important component of tumorigenesis and metabolic diseases. The roles of microRNA149* (miRNA149*) in inflammation remain poorly understood. Here, we demonstrate that miR-149* is a suppressor of STAT3-mediated inflammation. MiR-149*-/- mice were generated with CRISPR/CAS9 technique. In a lipopolysaccharide (LPS)-induced inflammation model, miR-149*-/- mice show more severe liver injury and inflammation, compared with wild-type (WT) mice. MiR-149*-/- mice also displayed elevated messenger RNA (mRNA) levels of interleukin (IL)-6, inducible nitric oxide synthase (iNOS), complement C3 (C3) and IL-4 in response to LPS...
June 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28627393/the-potential-and-challenges-of-crispr-cas-in-eradication-of-hepatitis-b-virus-covalently-closed-circular-dna
#18
REVIEW
Hung-Chih Yang, Pei-Jer Chen
Current antiviral therapy fails to cure chronic hepatitis B virus (HBV) infection, primarily because of the persistence of covalently closed circular DNA (cccDNA). Although nucleos(t)ide analogues (NAs) can inhibit the reverse transcriptase of HBV and suppress its replication to levels below the detection limit, viremia often rebounds after cessation of therapy. Nuclear cccDNA serves as the HBV replicative template and exhibits extraordinary stability, and is not affected by NAs. Therefore, curing chronic hepatitis B (CHB) requires novel therapy for purging cccDNA from patients...
June 13, 2017: Virus Research
https://www.readbyqxmd.com/read/28584302/crispr-cas9-mediated-p53-and-pten-dual-mutation-accelerates-hepatocarcinogenesis-in-adult-hepatitis-b-virus-transgenic-mice
#19
Yongzhen Liu, Xuewei Qi, Zhenzhen Zeng, Lu Wang, Jie Wang, Ting Zhang, Qiang Xu, Congle Shen, Guangde Zhou, Shaomin Yang, Xiangmei Chen, Fengmin Lu
The p53 mutation and altered Pten expression are two most common genetic events in Hepatitis B virus (HBV) infection related hepatocellular carcinoma (HCC). To confirm the causative role of p53 and Pten somatic mutation in HCC development, we established CRISPR/Cas9-mediated somatic gene disruption via hydrodynamic tail vein injection, allowing for in vivo targeting p53 and Pten simultaneously in adult HBV transgenic mice. Here we demonstrated that the utility of this approach resulted in macroscopic liver tumors as early as 4 months' post injection and most tumors harbored both p53 and Pten loss-of-function alterations...
June 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28574502/hepatitis-b-virus-x-protein-promotes-creb-mediated-activation-of-mir-3188-and-notch-signaling-in-hepatocellular-carcinoma
#20
Shao-Jun Zhou, Yue-Ling Deng, Hui-Fang Liang, Jonathan C Jaoude, Fu-Yao Liu
Familiar clustering of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) has been frequently reported. However, limited information is available about the underlying molecular mechanisms in HBV-related HCC patients with family history of HCC. In our previous study, Agilent miRNA Base 16.0 microarray showed miRNA profiles of the plasma of HBV-related HCC patients who had a family history of HCC. This study aims to explore the expression, function, and mechanisms of miR-3188 in HCC that might provide novel insights into the role of family history on the risk of HCC...
September 2017: Cell Death and Differentiation
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