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Crispr/cas9 hepatitis

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https://www.readbyqxmd.com/read/29769640/hypoxia-induced-microrna-191-contributes-to-hepatic-ischemia-reperfusion-injury-through-the-zonab-cyclin-d1-axis
#1
Wenming Pan, Lin Wang, Xiao-Fei Zhang, Hongji Zhang, Jinxiang Zhang, Guoliang Wang, Peng Xu, Yunwei Zhang, Ping Hu, Xiao-Dong Zhang, Run-Lei Du, Hui Wang
Hepatic ischemia/reperfusion injury (IRI) is a common cause of morbidity and mortality in liver transplantation settings and involves severe cell death and inflammatory responses. MicroRNA-191 has recently been reported to be abnormally expressed in hepatocellular carcinoma and other liver diseases in the regulation of important cellular processes. However, little is known about its function and molecular mechanism in IRI. Here, we demonstrate that miR-191 is significantly upregulated in a cultured cell line during hypoxia/reperfusion (H/R) and in liver tissue during IRI in mice...
May 16, 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29678421/growth-hormone-receptor-deficient-pigs-resemble-the-pathophysiology-of-human-laron-syndrome-and-reveal-altered-activation-of-signaling-cascades-in-the-liver
#2
Arne Hinrichs, Barbara Kessler, Mayuko Kurome, Andreas Blutke, Elisabeth Kemter, Maren Bernau, Armin M Scholz, Birgit Rathkolb, Simone Renner, Sebastian Bultmann, Heinrich Leonhardt, Martin Hrabĕ de Angelis, Hiroshi Nagashima, Andreas Hoeflich, Werner F Blum, Martin Bidlingmaier, Rüdiger Wanke, Maik Dahlhoff, Eckhard Wolf
OBJECTIVE: Laron syndrome (LS) is a rare, autosomal recessive disorder in humans caused by loss-of-function mutations of the growth hormone receptor (GHR) gene. To establish a large animal model for LS, pigs with GHR knockout (KO) mutations were generated and characterized. METHODS: CRISPR/Cas9 technology was applied to mutate exon 3 of the GHR gene in porcine zygotes. Two heterozygous founder sows with a 1-bp or 7-bp insertion in GHR exon 3 were obtained, and their heterozygous F1 offspring were intercrossed to produce GHR-KO, heterozygous GHR mutant, and wild-type pigs...
March 15, 2018: Molecular Metabolism
https://www.readbyqxmd.com/read/29599079/efficient-in-vivo-liver-directed-gene-editing-using-crispr-cas9
#3
Kshitiz Singh, Hanneke Evens, Nisha Nair, Melvin Y Rincón, Shilpita Sarcar, Ermira Samara-Kuko, Marinee K Chuah, Thierry VandenDriessche
In vivo tissue-specific genome editing at the desired loci is still a challenge. Here, we report that AAV9-delivery of truncated guide RNAs (gRNAs) and Cas9 under the control of a computationally designed hepatocyte-specific promoter lead to liver-specific and sequence-specific targeting in the mouse factor IX (F9) gene. The efficiency of in vivo targeting was assessed by T7E1 assays, site-specific Sanger sequencing, and deep sequencing of on-target and putative off-target sites. Though AAV9 transduction was apparent in multiple tissues and organs, Cas9 expression was restricted mainly to the liver, with only minimal or no expression in other non-hepatic tissues...
March 6, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29594458/host-genetics-in-malaria-lessons-from-mouse-studies
#4
REVIEW
Hong Ming Huang, Brendan J McMorran, Simon J Foote, Gaetan Burgio
Malaria remains a deadly parasitic disease caused by Plasmodium, claiming almost half a million lives every year. While parasite genetics and biology are often the major targets in many studies, it is becoming more evident that host genetics plays a crucial role in the outcome of the infection. Similarly, Plasmodium infections in mice also rely heavily on the genetic background of the mice, and often correlate with observations in human studies, due to their high genetic homology with humans. As such, murine models of malaria are a useful tool for understanding host responses during Plasmodium infections, as well as dissecting host-parasite interactions through various genetic manipulation techniques...
March 28, 2018: Mammalian Genome: Official Journal of the International Mammalian Genome Society
https://www.readbyqxmd.com/read/29545368/commd-family-regulates-plasma-ldl-levels-and-attenuates-atherosclerosis-through-stabilizing-the-ccc-complex-in-endosomal-ldlr-trafficking
#5
Alina Fedoseienko, Melinde Wijers, Justina C Wolters, Daphne Dekker, Marieke Smit, Nicolette Huijkman, Niels Kloosterhuis, Helene Klug, Aloys Schepers, Ko Willems van Dijk, Johannes H Levels, Daniel D Billadeau, Marten H Hofker, Jan van Deursen, Marit Westerterp, Ezra Burstein, Jan Albert Kuivenhoven, Bart van de Sluis
<u>Rationale:</u> <u>CO</u>pper <u>M</u>etabolism <u>M</u>URR1 Domain-containing (COMMD) proteins are a part of the COMMD-CCDC22-CCDC93 (CCC) complexes facilitating endosomal trafficking of cell surface receptors. Hepatic COMMD1 inactivation decreases CCDC22 and CCDC93 protein levels, impairs the recycling of the low-density lipoprotein receptor (LDLR), and increases plasma LDL cholesterol levels in mice. However, whether any of the other COMMD members function similarly as COMMD1, and whether perturbation in the CCC complex promotes atherogenesis remain unclear...
March 15, 2018: Circulation Research
https://www.readbyqxmd.com/read/29530977/regulation-of-hepatic-gluconeogenesis-by-nuclear-factor-y-transcription-factor-in-mice
#6
Yanjie Zhang, Qiuyue Guan, Yin Liu, Yuwei Zhang, Yulong Chen, Jinglu Chen, Yulan Liu, Zhiguang Su
Hepatic gluconeogenesis is essential to maintain blood glucose levels, and its abnormal activation leads to hyperglycemia and type 2 diabetes. However, the molecular mechanisms in the regulation of hepatic gluconeogenesis remain to be fully defined. In this study, using murine hepatocytes and a liver-specific knockout mouse model, we explored the physiological role of nuclear factor Y (NF-Y) in regulating hepatic glucose metabolism and the underlying mechanism. We found that NF-Y targets the gluconeogenesis pathway in the liver...
May 18, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29467456/genome-wide-crispr-screen-reveals-sgol1-as-a-druggable-target-of-sorafenib-treated-hepatocellular-carcinoma
#7
Weijian Sun, Bin He, Beng Yang, Wendi Hu, Shaobing Cheng, Heng Xiao, Zhengjie Yang, Xiaoyu Wen, Lin Zhou, Haiyang Xie, Xian Shen, Jian Wu, Shusen Zheng
The genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screen is a powerful tool used to identify therapeutic targets that can be harnessed for cancer treatment. This study aimed to assess the efficacy of genome-wide CRISPR screening to identify druggable genes associated with sorafenib-treated hepatocellular carcinoma (HCC). A genome-scale CRISPR knockout (GeCKO v2) library containing 123,411 single guide RNAs (sgRNAs) was used to identify loss-of-function mutations conferring sorafenib resistance upon HCC cells...
February 21, 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
https://www.readbyqxmd.com/read/29458131/inhibition-of-hepatitis-b-virus-replication-via-hbv-dna-cleavage-by-cas9-from-staphylococcus-aureus
#8
Yu Liu, Miaoxian Zhao, Mingxing Gong, Ying Xu, Cantao Xie, Haohui Deng, Xueying Li, Hongkai Wu, Zhanhui Wang
Chronic hepatitis B virus (HBV) infection is difficult to cure due to the presence of covalently closed circular DNA (cccDNA). Accumulating evidence indicates that the CRISPR/Cas9 system effectively disrupts HBV genome, including cccDNA, in vitro and in vivo. However, efficient delivery of CRISPR/Cas9 system to the liver or hepatocytes using an adeno-associated virus (AAV) vector remains challenging due to the large size of Cas9 from Streptococcus pyogenes (Sp). The recently identified Cas9 protein from Staphylococcus aureus (Sa) is smaller than SpCas9 and thus is able to be packaged into the AAV vector...
April 2018: Antiviral Research
https://www.readbyqxmd.com/read/29453277/editing-out-five-serpina1-paralogs-to-create-a-mouse-model-of-genetic-emphysema
#9
Florie Borel, Huaming Sun, Marina Zieger, Andrew Cox, Brynn Cardozo, Weiying Li, Gabriella Oliveira, Airiel Davis, Alisha Gruntman, Terence R Flotte, Michael H Brodsky, Andrew M Hoffman, Mai K Elmallah, Christian Mueller
Chronic obstructive pulmonary disease affects 10% of the worldwide population, and the leading genetic cause is α-1 antitrypsin (AAT) deficiency. Due to the complexity of the murine locus, which includes up to six Serpina1 paralogs, no genetic animal model of the disease has been successfully generated until now. Here we create a quintuple Serpina1a-e knockout using CRISPR/Cas9-mediated genome editing. The phenotype recapitulates the human disease phenotype, i.e., absence of hepatic and circulating AAT translates functionally to a reduced capacity to inhibit neutrophil elastase...
March 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29453099/impact-of-integrated-viral-dna-on-the-goal-to-clear-hepatitis-b-surface-antigen-with-different-therapeutic-strategies
#10
REVIEW
Magnus Lindh, Gustaf E Rydell, Simon B Larsson
A hallmark of hepatitis B virus (HBV) infection is the presence of hepatitis B surface antigen (HBsAg) in the serum of patients. Sustained loss of HBV DNA and HBsAg from the blood are main goals for treatment, and considered as functional cure. It is rarely achieved with long-term nucleoside analogue treatment though, both because cccDNA, the template for viral replication, is not completely cleared, and probably also because hepatocytes with HBV DNA integrated into their chromosomes persist and continue to produce large amounts of HBsAg...
February 13, 2018: Current Opinion in Virology
https://www.readbyqxmd.com/read/29427479/towards-hbv-curative-therapies
#11
REVIEW
Raymond F Schinazi, Maryam Ehteshami, Leda Bassit, Tarik Asselah
Tremendous progress has been made over the last 2 decades to discover and develop approaches to control hepatitis B virus (HBV) infections and to prevent the development of hepatocellular carcinoma using various interferons and small molecules as antiviral agents. However, none of these agents have significant impact on eliminating HBV from infected cells. Currently the emphasis is on silencing or eliminating cccDNA, which could lead to a cure for HBV. Various approaches are being developed including the development of capsid effectors, CRISPR/Cas9, TALENS, siRNA, entry and secretion inhibitors, as well as immunological approaches...
February 2018: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/29343656/crispr-cas9-mediated-generation-of-obese-and-diabetic-mouse-models
#12
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
#13
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...
January 2018: EBioMedicine
https://www.readbyqxmd.com/read/29277559/pan-genotype-hepatitis-e-virus-replication-in-stem-cell-derived-hepatocellular-systems
#14
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...
February 2018: Gastroenterology
https://www.readbyqxmd.com/read/29259521/nuclease-mediated-gene-therapies-for-inherited-metabolic-diseases-of-the-liver
#15
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
#16
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
#17
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...
February 2018: 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
#18
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
#19
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
#20
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
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