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Crispr/cas9 hepatitis

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https://www.readbyqxmd.com/read/28300165/somatic-genome-editing-with-crispr-cas9-generates-and-corrects-a-metabolic-disease
#1
Kelsey E Jarrett, Ciaran M Lee, Yi-Hsien Yeh, Rachel H Hsu, Rajat Gupta, Min Zhang, Perla J Rodriguez, Chang Seok Lee, Baiba K Gillard, Karl-Dimiter Bissig, Henry J Pownall, James F Martin, Gang Bao, William R Lagor
Germline manipulation using CRISPR/Cas9 genome editing has dramatically accelerated the generation of new mouse models. Nonetheless, many metabolic disease models still depend upon laborious germline targeting, and are further complicated by the need to avoid developmental phenotypes. We sought to address these experimental limitations by generating somatic mutations in the adult liver using CRISPR/Cas9, as a new strategy to model metabolic disorders. As proof-of-principle, we targeted the low-density lipoprotein receptor (Ldlr), which when deleted, leads to severe hypercholesterolemia and atherosclerosis...
March 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28282856/hepatitis-b-virus-x-protein-stimulates-proliferation-wound-closure-and-inhibits-apoptosis-of-huh-7-cells-via-cdc42
#2
Yongru Xu, Yingzi Qi, Jing Luo, Jing Yang, Qi Xie, Chen Deng, Na Su, Wei Wei, Deshun Shi, Feng Xu, Xiangping Li, Ping Xu
Chronic hepatitis B virus (HBV) infection has been considered as the major cause of hepatocellular carcinoma (HCC). Hepatitis B virus X protein (HBx) has been reported to be oncogenic. The underlying mechanisms of HBV-related HCC are not fully understood, and the role played by the HBx protein in HBV induced carcinogenesis remains controversial. CDC42, a member of the Rho GTPase family, has been reported to be overexpressed in several different cancers, including HBV-related HCC. However, the specific role of CDC42 in HCC development remains unclear...
March 8, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28087399/advances-with-using-crispr-cas-mediated-gene-editing-to-treat-infections-with-hepatitis-b-virus-and-hepatitis-c-virus
#3
REVIEW
Buhle Moyo, Kristie Bloom, Tristan Scott, Abdullah Ely, Patrick Arbuthnot
Chronic infections with hepatitis B and hepatitis C viruses (HBV and HCV) account for the majority of cases of cirrhosis and hepatocellular carcinoma. Current therapies for the infections have limitations and improved efficacy is necessary to prevent complications in carriers of the viruses. In the case of HBV persistence, the replication intermediate comprising covalently closed circular DNA (cccDNA) is particularly problematic. Licensed therapies have little effect on cccDNA and HBV replication relapses following treatment withdrawal...
January 10, 2017: Virus Research
https://www.readbyqxmd.com/read/27935189/epigenetic-regulation-of-the-glucose-transporter-gene-slc2a1-by-%C3%AE-hydroxybutyrate-underlies-preferential-glucose-supply-to-the-brain-of-fasted-mice
#4
Kosuke Tanegashima, Yukiko Sato-Miyata, Masabumi Funakoshi, Yasumasa Nishito, Toshiro Aigaki, Takahiko Hara
We carried out liquid chromatography-tandem mass spectrometry analysis of metabolites in mice. Those metabolome data showed that hepatic glucose content is reduced, but that brain glucose content is unaffected, during fasting, consistent with the priority given to brain glucose consumption during fasting. The molecular mechanisms for this preferential glucose supply to the brain are not fully understood. We also showed that the fasting-induced production of the ketone body β-hydroxybutyrate (β-OHB) enhances expression of the glucose transporter gene Slc2a1 (Glut1) via histone modification...
January 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/27929099/stat1-is-essential-for-the-inhibition-of-hepatitis-c-virus-replication-by-interferon-%C3%AE-but-not-by-interferon-%C3%AE
#5
Shota Yamauchi, Kenji Takeuchi, Kazuyasu Chihara, Chisato Honjoh, Yuji Kato, Hatsumi Yoshiki, Hak Hotta, Kiyonao Sada
Interferon-α (IFN-α) and IFN-λ are structurally distinct cytokines that bind to different receptors, but induce expression of similar sets of genes through Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathways. The difference between IFN-α and IFN-λ signaling remains poorly understood. Here, using the CRISPR/Cas9 system, we examine the role of STAT1 and STAT2 in the inhibition of hepatitis C virus (HCV) replication by IFN-α and IFN-λ. Treatment with IFN-α increases expression of IFN-stimulated genes (ISGs) such as double-stranded RNA-activated protein kinase (PKR) and decreases viral RNA and protein levels in HCV-infected Huh-7...
December 8, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27917363/future-therapy-for-hepatitis-b-virus-role-of-immunomodulators
#6
REVIEW
Edward A Pham, Ryan B Perumpail, Benjamin J Fram, Jeffrey S Glenn, Aijaz Ahmed, Robert G Gish
Although currently available therapies for chronic hepatitis B virus infection can suppress viremia and provide long-term benefits for patients, they do not lead to a functional cure for most patients. Advances in our understanding of the virus-host interaction and the recent remarkable success of immunotherapy in cancer offer new and promising strategies for developing immune modulators that may become important components of a total therapeutic approach to hepatitis B, some of which are now in clinical development...
2016: Current Hepatology Reports
https://www.readbyqxmd.com/read/27860197/crispr-cas9-the-ultimate-weapon-to-battle-infectious-diseases
#7
REVIEW
M Doerflinger, W Forsyth, G Ebert, M Pellegrini, M J Herold
Infectious diseases are a leading cause of death worldwide. Novel therapeutics are urgently required to treat multidrug-resistant organisms such as Mycobacterium tuberculosis and to mitigate morbidity and mortality caused by acute infections such as malaria and dengue fever virus as well as chronic infections such as human immunodeficiency virus-1 and hepatitis B virus. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system, which has revolutionized biomedical research, holds great promise for the identification and validation of novel drug targets...
November 16, 2016: Cellular Microbiology
https://www.readbyqxmd.com/read/27783675/dna-polymerase-%C3%AE%C2%BA-is-a-key-cellular-factor-for-the-formation-of-covalently-closed-circular-dna-of-hepatitis-b-virus
#8
Yonghe Qi, Zhenchao Gao, Guangwei Xu, Bo Peng, Chenxuan Liu, Huan Yan, Qiyan Yao, Guoliang Sun, Yang Liu, Dingbin Tang, Zilin Song, Wenhui He, Yinyan Sun, Ju-Tao Guo, Wenhui Li
Hepatitis B virus (HBV) infection of hepatocytes begins by binding to its cellular receptor sodium taurocholate cotransporting polypeptide (NTCP), followed by the internalization of viral nucleocapsid into the cytoplasm. The viral relaxed circular (rc) DNA genome in nucleocapsid is transported into the nucleus and converted into covalently closed circular (ccc) DNA to serve as a viral persistence reservoir that is refractory to current antiviral therapies. Host DNA repair enzymes have been speculated to catalyze the conversion of rcDNA to cccDNA, however, the DNA polymerase(s) that fills the gap in the plus strand of rcDNA remains to be determined...
October 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27708159/insulin-resistance-and-diabetes-caused-by-genetic-or-diet-induced-kbtbd2-deficiency-in-mice
#9
Zhao Zhang, Emre Turer, Xiaohong Li, Xiaoming Zhan, Mihwa Choi, Miao Tang, Amanda Press, Steven R Smith, Adeline Divoux, Eva Marie Y Moresco, Bruce Beutler
We describe a metabolic disorder characterized by lipodystrophy, hepatic steatosis, insulin resistance, severe diabetes, and growth retardation observed in mice carrying N-ethyl-N-nitrosourea (ENU)-induced mutations. The disorder was ascribed to a mutation of kelch repeat and BTB (POZ) domain containing 2 (Kbtbd2) and was mimicked by a CRISPR/Cas9-targeted null allele of the same gene. Kbtbd2 encodes a BTB-Kelch family substrate recognition subunit of the Cullin-3-based E3 ubiquitin ligase. KBTBD2 targeted p85α, the regulatory subunit of the phosphoinositol-3-kinase (PI3K) heterodimer, causing p85α ubiquitination and proteasome-mediated degradation...
October 18, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27659023/highly-multiplexed-crispr-cas9-nuclease-and-cas9-nickase-vectors-for-inactivation-of-hepatitis-b-virus
#10
Tetsushi Sakuma, Keiichi Masaki, Hiromi Abe-Chayama, Keiji Mochida, Takashi Yamamoto, Kazuaki Chayama
CRISPR-Cas9-mediated genome-editing technology contributes not only to basic genomic studies but also to clinical studies such as genetic correction and virus inactivation. Hepatitis B virus (HBV) is a major target for potential application of CRISPR-Cas9 in eliminating viral DNA from human cells. However, the high stability of covalently closed circular DNA (cccDNA) makes it difficult to completely clear HBV infection. Here, we report highly multiplexed CRISPR-Cas9-nuclease and Cas9-nickase vector systems that simultaneously target three critical domains of the HBV genome...
November 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/27614072/talen-crispr-mediated-engineering-of-a-promoterless-anti-viral-rnai-hairpin-into-an-endogenous-mirna-locus
#11
Elena Senís, Stefan Mockenhaupt, Daniel Rupp, Tobias Bauer, Nagarajan Paramasivam, Bettina Knapp, Jan Gronych, Stefanie Grosse, Marc P Windisch, Florian Schmidt, Fabian J Theis, Roland Eils, Peter Lichter, Matthias Schlesner, Ralf Bartenschlager, Dirk Grimm
Successful RNAi applications depend on strategies allowing robust and persistent expression of minimal gene silencing triggers without perturbing endogenous gene expression. Here, we propose a novel avenue which is integration of a promoterless shmiRNA, i.e. a shRNA embedded in a micro-RNA (miRNA) scaffold, into an engineered genomic miRNA locus. For proof-of-concept, we used TALE or CRISPR/Cas9 nucleases to site-specifically integrate an anti-hepatitis C virus (HCV) shmiRNA into the liver-specific miR-122/hcr locus in hepatoma cells, with the aim to obtain cellular clones that are genetically protected against HCV infection...
January 9, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/27585307/crispr-cas9-technology-targeting-fas-gene-protects-mice-from-concanavalin-a-induced-fulminant-hepatic-failure
#12
Wei-Cheng Liang, Pu-Ping Liang, Cheuk-Wa Wong, Tzi-Bun Ng, Jun-Jiu Huang, Jin-Fang Zhang, Mary Miu-Yee Waye, Wei-Ming Fu
Fulminant hepatic failure is a life-threatening disease which occurs in patients without preexisting liver disease. Nowadays, there is no ideal therapeutic tool in the treatment of fulminant hepatic failure. Recent studies suggested that a novel technology termed CRISPR/Cas9 may be a promising approach for the treatment of fulminant hepatic failure. In this project, we have designed single chimeric guide RNAs specifically targeting the genomic regions of mouse Fas gene. The in vitro and in vivo effects of sgRNAs on the production of Fas protein were examined in cultured mouse cells and in a hydrodynamic injection-based mouse model, respectively...
September 1, 2016: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/27570484/an-effective-molecular-target-site-in-hepatitis-b-virus-s-gene-for-cas9-cleavage-and-mutational-inactivation
#13
Hao Li, Chunyu Sheng, Hongbo Liu, Guangze Liu, Xinying Du, Juan Du, Linsheng Zhan, Peng Li, Chaojie Yang, Lihua Qi, Jian Wang, Xiaoxia Yang, Leili Jia, Jing Xie, Ligui Wang, Rongzhang Hao, Dongping Xu, Yigang Tong, Yusen Zhou, Jianjun Zhou, Yansong Sun, Qiao Li, Shaofu Qiu, Hongbin Song
Chronic hepatitis B infection remains incurable because HBV cccDNA can persist indefinitely in patients recovering from acute HBV infection. Given the incidence of HBV infection and the shortcomings of current therapeutic options, a novel antiviral strategy is urgently needed. To inactivate HBV replication and destroy the HBV genome, we employed genome editing tool CRISPR/Cas9. Specifically, we found a CRISPR/Cas9 system (gRNA-S4) that effectively targeted the HBsAg region and could suppress efficiently viral replication with minimal off-target effects and impact on cell viability...
2016: International Journal of Biological Sciences
https://www.readbyqxmd.com/read/27383988/a-crispr-screen-defines-a-signal-peptide-processing-pathway-required-by-flaviviruses
#14
Rong Zhang, Jonathan J Miner, Matthew J Gorman, Keiko Rausch, Holly Ramage, James P White, Adam Zuiani, Ping Zhang, Estefania Fernandez, Qiang Zhang, Kimberly A Dowd, Theodore C Pierson, Sara Cherry, Michael S Diamond
Flaviviruses infect hundreds of millions of people annually, and no antiviral therapy is available. We performed a genome-wide CRISPR/Cas9-based screen to identify host genes that, when edited, resulted in reduced flavivirus infection. Here, we validated nine human genes required for flavivirus infectivity, and these were associated with endoplasmic reticulum functions including translocation, protein degradation, and N-linked glycosylation. In particular, a subset of endoplasmic reticulum-associated signal peptidase complex (SPCS) proteins was necessary for proper cleavage of the flavivirus structural proteins (prM and E) and secretion of viral particles...
July 7, 2016: Nature
https://www.readbyqxmd.com/read/27291420/hyperlipidemia-and-hepatitis-in-liver-specific-creb3l3-knockout-mice-generated-using-a-one-step-crispr-cas9-system
#15
Yoshimi Nakagawa, Fusaka Oikawa, Seiya Mizuno, Hiroshi Ohno, Yuka Yagishita, Aoi Satoh, Yoshinori Osaki, Kenta Takei, Takuya Kikuchi, Song-Iee Han, Takashi Matsuzaka, Hitoshi Iwasaki, Kazuto Kobayashi, Shigeru Yatoh, Naoya Yahagi, Masaaki Isaka, Hiroaki Suzuki, Hirohito Sone, Satoru Takahashi, Nobuhiro Yamada, Hitoshi Shimano
cAMP responsive element binding protein 3-like 3 (CREB3L3), a transcription factor expressed in the liver and small intestine, governs fasting-response energy homeostasis. Tissue-specific CREB3L3 knockout mice have not been generated till date. To our knowledge, this is the first study using the one-step CRISPR/Cas9 system to generate CREB3L3 floxed mice and subsequently obtain liver- and small intestine-specific Creb3l3 knockout (LKO and IKO, respectively) mice. While LKO mice as well as global KO mice developed hypertriglyceridemia, LKO mice exhibited hypercholesterolemia in contrast to hypocholesterolemia in global KO mice...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27203444/complete-spectrum-of-crispr-cas9-induced-mutations-on-hbv-cccdna
#16
Christoph Seeger, Ji A Sohn
Hepatitis B virus (HBV) causes chronic infections that cannot yet be cured. The virus persists in infected hepatocytes, because covalently closed circular DNA (cccDNA), the template for the transcription of viral RNAs, is stable in nondividing cells. Antiviral therapies with nucleoside analogues inhibit HBV DNA synthesis in capsids in the cytoplasm of infected hepatocytes, but do not destroy nuclear cccDNA. Because over 200 million people are still infected, a cure for chronic hepatitis B (CHB) has become one of the major challenges in antiviral therapy...
August 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27138846/efficient-and-controlled-generation-of-2d-and-3d-bile-duct-tissue-from-human-pluripotent-stem-cell-derived-spheroids
#17
Lipeng Tian, Abhijeet Deshmukh, Zhaohui Ye, Yoon-Young Jang
While in vitro liver tissue engineering has been increasingly studied during the last several years, presently engineered liver tissues lack the bile duct system. The lack of bile drainage not only hinders essential digestive functions of the liver, but also leads to accumulation of bile that is toxic to hepatocytes and known to cause liver cirrhosis. Clearly, generation of bile duct tissue is essential for engineering functional and healthy liver. Differentiation of human induced pluripotent stem cells (iPSCs) to bile duct tissue requires long and/or complex culture conditions, and has been inefficient so far...
August 2016: Stem Cell Reviews
https://www.readbyqxmd.com/read/27049051/crispr-cas9-produces-anti-hepatitis-b-virus-effect-in-hepatoma-cells-and-transgenic-mouse
#18
Wei Zhu, Kun Xie, Yuanjian Xu, Le Wang, Kaiming Chen, Longzhen Zhang, Jianmin Fang
Chronic infection of hepatitis B virus (HBV) is at risk of liver cirrhosis and hepatocellular carcinoma and remains one of the major public health problems worldwide. It is a major barrier of persistence HBV cccDNA under current antiviral therapy as novel strategies of disrupting HBV cccDNA is pressing. The (CRISPR)/Cas9 system is presently emerging in gene editing and we also apply it for targeting and deleting the conserved regions of HBV genome. Two homologous sequences of HBV S and X genes were carried with CRISPR/Cas9 endonuclease to build pCas9 constructs, which may mediate anti-HBV effects of in vitro and in vivo systems in this study...
June 2, 2016: Virus Research
https://www.readbyqxmd.com/read/26964564/crispr-cas9-mediated-somatic-correction-of-a-novel-coagulator-factor-ix-gene-mutation-ameliorates-hemophilia-in-mouse
#19
Yuting Guan, Yanlin Ma, Qi Li, Zhenliang Sun, Lie Ma, Lijuan Wu, Liren Wang, Li Zeng, Yanjiao Shao, Yuting Chen, Ning Ma, Wenqing Lu, Kewen Hu, Honghui Han, Yanhong Yu, Yuanhua Huang, Mingyao Liu, Dali Li
The X-linked genetic bleeding disorder caused by deficiency of coagulator factor IX, hemophilia B, is a disease ideally suited for gene therapy with genome editing technology. Here, we identify a family with hemophilia B carrying a novel mutation, Y371D, in the human F9 gene. The CRISPR/Cas9 system was used to generate distinct genetically modified mouse models and confirmed that the novel Y371D mutation resulted in a more severe hemophilia B phenotype than the previously identified Y371S mutation. To develop therapeutic strategies targeting this mutation, we subsequently compared naked DNA constructs versus adenoviral vectors to deliver Cas9 components targeting the F9 Y371D mutation in adult mice...
2016: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/26774178/hepatic-transmembrane-6-superfamily-member-2-regulates-cholesterol-metabolism-in-mice
#20
Yanbo Fan, Haocheng Lu, Yanhong Guo, Tianqing Zhu, Minerva T Garcia-Barrio, Zhisheng Jiang, Cristen J Willer, Jifeng Zhang, Y Eugene Chen
BACKGROUND & AIMS: The rs58542926 C>T variant of the transmembrane 6 superfamily member 2 gene (TM6SF2), encoding an E167K amino acid substitution, has been correlated with reduced total cholesterol (TC) and cardiovascular disease. However, little is known about the role of TM6SF2 in metabolism. We investigated the long-term effects of altered TM6SF2 levels in cholesterol metabolism. METHODS: C57BL/6 mice (controls), mice that expressed TM6SF2 specifically in the liver, and mice with CRISPR/Cas9-mediated knockout of Tm6sf2 were fed chow or high-fat diets...
May 2016: Gastroenterology
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