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CRISPR AND animal Models

Shaina N Porter, Rachel M Levine, Shondra M Pruett-Miller
Genome engineering using programmable nucleases is a rapidly evolving technique that enables precise genetic manipulations within complex genomes. Although this technology first surfaced with the creation of meganucleases, zinc finger nucleases, and transcription activator-like effector nucleases, CRISPR-Cas9 has been the most widely adopted platform because of its ease of use. This comprehensive review presents a basic overview of genome engineering and discusses the major technological advances in the field...
March 14, 2019: Comprehensive Physiology
Chunlong Xu, Sen Wu, Lawrence B Schook, Kyle M Schachtschneider
The global incidence of cancer is rapidly rising, and despite an improved understanding of cancer molecular biology, immune landscapes, and advancements in cytotoxic, biologic, and immunologic anti-cancer therapeutics, cancer remains a leading cause of death worldwide. Cancer is caused by the accumulation of a series of gene mutations called driver mutations that confer selective growth advantages to tumor cells. As cancer therapies move toward personalized medicine, predictive modeling of the role driver mutations play in tumorigenesis and therapeutic susceptibility will become essential...
2019: Frontiers in Oncology
Giorgia Girotto, Anna Morgan, Navaneethakrishnan Krishnamoorthy, Massimiliano Cocca, Marco Brumat, Sissy Bassani, Martina La Bianca, Mariateresa Di Stazio, Paolo Gasparini
Age-related hearing loss (ARHL) is the most common sensory impairment in the elderly affecting millions of people worldwide. To shed light on the genetics of ARHL, a large cohort of 464 Italian patients has been deeply characterized at clinical and molecular level. In particular, 46 candidate genes, selected on the basis of genome-wide association studies (GWAS), animal models and literature updates, were analyzed by targeted re-sequencing. After filtering and prioritization steps, SLC9A3R1 has been identified as a strong candidate and then validated by " in vitro" and "in vivo" studies...
2019: Frontiers in Genetics
Anna Saborowski, Katharina Wolff, Steffi Spielberg, Benedikt Beer, Björn Hartleben, Zulrahman Erlangga, Diana Becker, Lukas E Dow, Silke Marhenke, Norman Woller, Kristian Unger, Peter Schirmacher, Michael P Manns, Jens U Marquardt, Arndt Vogel, Michael Saborowski
The rising incidence of cholangiocarcinoma (CCA) coupled with a low 5-year survival rate that remains below 10% delineates the urgent need for more effective treatment strategies. Although several recent studies provided detailed information on the genetic landscape of this fatal malignancy, versatile model systems to functionally dissect the immediate clinical relevance of the identified genetic alterations are still missing. To enhance our understanding of CCA pathophysiology and facilitate rapid functional annotation of putative CCA driver and tumor maintenance genes, we developed a tractable murine CCA model by combining the cyclization recombination (Cre)-lox system, RNA interference, and clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) technology with liver organoids, followed by subsequent transplantation into immunocompetent, syngeneic mice...
March 2019: Hepatology Communications
David M German, Shoukhrat Mitalipov, Anusha Mishra, Sanjiv Kaul
A variety of genetic cardiovascular diseases may one day be curable using gene editing technology. Germline genome editing and correction promises to permanently remove monogenic cardiovascular disorders from the offspring and subsequent generations of affected families. Although technically feasible and likely to be ready for implementation in humans in the near future, this approach remains ethically controversial. Although currently beset by several technical challenges, and not yet past small animal models, somatic genome editing may also be useful for a variety of cardiovascular disorders...
February 2019: JACC. Basic to Translational Science
Xi Qin, Wenrong Yao, Xinchang Shi, Lan Liu, Fang Huang, Youxue Ding, Yong Zhou, Lei Yu, Chuncui Jia, Shanhu Li, Chunming Rao, Junzhi Wang
Bioassay of recombinant protein products is important tests to ensure protein effectiveness. Some recombinant protein products have no cells used in their bioassay but instead use animal models, while others have no suitable method. Here, we developed a method to obtain responsive cells used in bioassay of proteins. After screening of a CRISPR/Cas9 library, we obtained a responsive cell line that grew faster in the presence of rhEGF (recombinant human epidermal growth factor) than that of control cells. We used this cell line for bioassay of rhEGF...
March 7, 2019: Scientific Reports
Min Wu, Ye Feng, Guo-Xin Ye, Yu-Chen Han, Si-Si Wang, Hai Feng Ni, Feng-Mei Wang, Min Gao, Lin-Li Lv, Bi-Cheng Liu
Experimental studies showed that pharmacological activation of calcium-sensing receptor (CaSR) attenuated renal fibrosis in some animal models beyond modification of bone and mineral homeostasis; however, its underlying mechanisms remain largely unknown. Since excessive collagen deposition is the key feature of fibrosis, the present study aimed to examine whether CaSR was involved in the regulation of collagen expression in rats with adenine diet (AD)-induced renal fibrosis and in profibrotic TGF-β1-treated renal proximal tubular epithelial cells (PTECs)...
March 6, 2019: American Journal of Physiology. Renal Physiology
Jaesuk Lee, Delger Bayarsaikhan, Roshini Arivazhagan, Hyejung Park, Byungyoon Lim, Peter Gwak, Goo-Bo Jeong, Jaewon Lee, Kyunghee Byun, Bonghee Lee
Background and Objectives: Parkinson's disease (PD) is a fatal and progressive degenerative disease of the nervous system. Until recently, its promising treatment and underlying mechanisms for neuronal death are poorly understood. This study was investigated to identify the molecular mechanism of neuronal death in the substantia nigra and corpus striatum of PD. Methods: The soluble RAGE (sRAGE) secreting Umbilical Cord Blood-derived Mesenchymal Stem Cell (UCB-MSC) was generated by gene editing method using clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9)...
February 28, 2019: International Journal of Stem Cells
Diana Raquel Rodríguez-Rodríguez, Ramiro Ramírez-Solís, Mario Alberto Garza-Elizondo, María De Lourdes Garza-Rodríguez, Hugo Alberto Barrera-Saldaña
Genome editing reemerged in 2012 with the development of CRISPR/Cas9 technology, which is a genetic manipulation tool derived from the defense system of certain bacteria against viruses and plasmids. This method is easy to apply and has been used in a wide variety of experimental models, including cell lines, laboratory animals, plants, and even in human clinical trials. The CRISPR/Cas9 system consists of directing the Cas9 nuclease to create a site‑directed double‑strand DNA break using a small RNA molecule as a guide...
February 26, 2019: International Journal of Molecular Medicine
Xiayin Zhang, Dongni Wang, Meimei Dongye, Yi Zhu, Chuan Chen, Ruixin Wang, Erping Long, Zhenzhen Liu, Xiaohang Wu, Duoru Lin, Jingjing Chen, Zhuoling Lin, Jinghui Wang, Wangting Li, Yang Li, Dongmei Li, Haotian Lin
Cryptophthalmos is a rare congenital disorder characterized by ocular dysplasia with eyelid malformation. Complete cryptophthalmos is characterized by the presence of continuous skin from the forehead over the eyes and onto the cheek, along with complete fusion of the eyelids. In the present study, we characterized the clinical manifestations of three patients with isolated bilateral cryptophthalmos. These patients shared the same c.6499C > T missense mutation in the FRAS1-related extracellular matrix protein 2 (FREM2) gene, while each individual presented an additional nonsense mutation in the same gene (Patient #1, c...
February 22, 2019: Experimental Eye Research
Jong Geol Lee, Chang Hoon Ha, Bohyun Yoon, Seung-A Cheong, Globinna Kim, Doo Jae Lee, Dong-Cheol Woo, Young-Hak Kim, Sang-Yoon Nam, Sang-Wook Lee, Young Hoon Sung, In-Jeoung Baek
The rat is a time-honored traditional experimental model animal, but its use is limited due to the difficulty of genetic modification. Although engineered endonucleases enable us to manipulate the rat genome, it is not known whether the newly identified endonuclease Cpf1 system is applicable to rats. Here we report the first application of CRISPR-Cpf1 in rats and investigate whether Apoe knockout rat can be used as an atherosclerosis model. We generated Apoe- and/or Ldlr-deficient rats via CRISPR-Cpf1 system, characterized by high efficiency, successful germline transmission, multiple gene targeting capacity, and minimal off-target effect...
February 22, 2019: Scientific Reports
Haris Babačić, Aditi Mehta, Olivia Merkel, Benedikt Schoser
INTRODUCTION: The system of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (cas) is a new technology that allows easier manipulation of the genome. Its potential to edit genes opened a new door in treatment development for incurable neurological monogenic diseases (NMGDs). The aim of this systematic review was to summarise the findings on the current development of CRISPR-cas for therapeutic purposes in the most frequent NMGDs and provide critical assessment...
2019: PloS One
Susanne Bäck, Julie Necarsulmer, Leslie R Whitaker, Lamarque M Coke, Pyry Koivula, Emily J Heathward, Lowella V Fortuno, Yajun Zhang, C Grace Yeh, Heather A Baldwin, Morgan D Spencer, Carlos A Mejias-Aponte, James Pickel, Alexander F Hoffman, Charles E Spivak, Carl R Lupica, Suzanne M Underhill, Susan G Amara, Andrii Domanskyi, Jenni E Anttila, Mikko Airavaara, Bruce T Hope, F Kent Hamra, Christopher T Richie, Brandon K Harvey
Historically, the rat has been the preferred animal model for behavioral studies. Limitations in genome modification have, however, caused a lag in their use compared to the bevy of available transgenic mice. Here, we have developed several transgenic tools, including viral vectors and transgenic rats, for targeted genome modification in specific adult rat neurons using CRISPR-Cas9 technology. Starting from wild-type rats, knockout of tyrosine hydroxylase was achieved with adeno-associated viral (AAV) vectors expressing Cas9 or guide RNAs (gRNAs)...
February 8, 2019: Neuron
Ali Zarei, Vahid Razban, Seyed Ebrahim Hosseini, Seyed Mohammad Bagher Tabei
AIMS: Set of unique sequences in bacterial genomes, responsible for protecting bacteria against bacteriophages, have been recently used for genetic manipulation of specific points in the genome. These system comprises of one RNA component and one enzyme component, known as CRISPR and Cas9, respectively. The present review focuses on the applications of the CRISPR/Cas9 technology in the development of cellular and animal models of human disease. DISCUSSION: Making a desired genetic alteration depend on the design of RNA molecules that guide endonucleases to a favorable genomic location...
February 20, 2019: Journal of Gene Medicine
Miao Yu, Xingshen Sun, Scott R Tyler, Bo Liang, Anthony M Swatek, Thomas J Lynch, Nan He, Feng Yuan, Zehua Feng, Pavana G Rotti, Soon H Choi, Weam Shahin, Xiaoming Liu, Ziying Yan, John F Engelhardt
The domestic ferret (Mustela putorius furo) has proven to be a useful species for modeling human genetic and infectious diseases of the lung and brain. However, biomedical research in ferrets has been hindered by the lack of rapid and cost-effective methods for genome engineering. Here, we utilized CRISPR/Cas9-mediated, homology-independent insertion at the ROSA26 "safe harbor" locus in ferret zygotes and created transgenic animals expressing a dual-fluorescent Cre-reporter system flanked by PhiC31 and Bxb1 integrase attP sites...
February 13, 2019: Scientific Reports
Nan He, Bradley H Rosen, Jaimie S Gray, Idil A Evans, Marina Zieger, Ziying Yan, Florie Borel, Bo Liang, Xingshen Sun, Shashanna R Moll, Michael H Brodsky, Christian Mueller, John F Engelhardt
RATIONALE: The most prevalent genetic cause of chronic obstructive pulmonary disease is alpha-1 antitrypsin (A1AT) deficiency, a disorder that has yet to be widely modeled in animals because of species-specific differences between rodents and humans. OBJECTIVES: To address these challenges, we engineered two A1AT ferret models using zygote gene editing to test the hypothesis that unopposed protease activity within the lung leads to emphysema and bronchitis. METHODS: Guide RNAs targeting exon 2 (for knockout) and exon 5 (for Z-allele mutation, Pi*Z) of the ferret A1AT gene were injected into ferret zygotes with Cas9 mRNA...
December 2018: Annals of the American Thoracic Society
Elaine M Morazzani, Jaimee R Compton, Dagmar H Leary, Angela V Berry, Xin Hu, Juan Marugan, Pamela J Glass, Patricia M Legler
The alphaviral nonstructural protein 2 (nsP2) cysteine proteases (EC 3.4.22.-) are essential for the proteolytic processing of the nonstructural (ns) polyprotein and are validated drug targets. A common secondary role of these proteases is to antagonize the effects of interferon (IFN). After delineating the cleavage site motif of the Venezuelan equine encephalitis virus (VEEV) nsP2 cysteine protease, we searched the human genome to identify host protein substrates. Here we identify a new host substrate of the VEEV nsP2 protease, human TRIM14, a component of the mitochondrial antiviral-signaling protein (MAVS) signalosome...
February 8, 2019: Antiviral Research
Xiaoling Jiang, Huazhen Liu, Yongxian Shao, Mingzhi Peng, Wen Zhang, Duan Li, Xiuzhen Li, Yanna Cai, Ting Tan, Xinshuo Lu, Jianan Xu, Xueying Su, Yunting Lin, Zongcai Liu, Yonglan Huang, Chunhua Zeng, Ya-Ping Tang, Li Liu
BACKGROUND: GTP cyclohydrolase I (GTPCH) deficiency could impair the synthesis of tetrahydrobiopterin and causes metabolic diseases involving phenylalanine catabolism, neurotransmitter synthesis, nitric oxide production and so on. Though improvements could be achieved by tetrahydrobiopterin and neurotransmitter precursor levodopa supplementation, residual motor and mental deficits remain in some patients. An appropriate GTPCH deficiency animal model with clinical symptoms, especially the motor impairments, is still not available for mechanism and therapy studies yet...
February 8, 2019: Metabolism: Clinical and Experimental
A Scott Emmert, Shawn M Vuong, Crystal Shula, Diana Lindquist, Weihong Yuan, Yueh-Chiang Hu, Francesco T Mangano, June Goto
OBJECTIVEEmergence of CRISPR/Cas9 genome editing provides a robust method for gene targeting in a variety of cell types, including fertilized rat embryos. The authors used this method to generate a transgenic rat L1cam knockout model of X-linked hydrocephalus (XLH) with human genetic etiology. The object of this study was to use diffusion tensor imaging (DTI) in studying perivascular white matter tract injury in the rat model and to characterize its pathological definition in histology.METHODSTwo guide RNAs designed to disrupt exon 4 of the L1cam gene on the X chromosome were injected into Sprague-Dawley rat embryos...
February 8, 2019: Journal of Neurosurgery
Kengo Horie, Kiyoshi Inoue, Shingo Suzuki, Saki Adachi, Saori Yada, Takashi Hirayama, Shizu Hidema, Larry J Young, Katsuhiko Nishimori
Behavioral neuroendocrinology has benefited tremendously from the use of a wide range of model organisms that are ideally suited for particular questions. However, in recent years the ability to manipulate the genomes of laboratory strains of mice has led to rapid advances in our understanding of the role of specific genes, circuits and neural populations in regulating behavior. While genome manipulation in mice has been a boon for behavioral neuroscience, the intensive focus on the mouse restricts the diversity in behavioral questions that can be investigated using state-of-the-art techniques...
November 8, 2018: Hormones and Behavior
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