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Journal articles on the topic 'Knockin mouse model'

Author: Grafiati

Published: 18 May 2024

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1

Savva, Isavella, Charalampos Stefanou, Myrtani Pieri, Dorin B. Borza, Kostas Stylianou, George Lapathitis, Christos Karaiskos, Gregoris Papagregoriou, and Constantinos Deltas. "MP036A NOVEL KNOCKIN MOUSE MODEL FOR ALPORT SYNDROME." Nephrology Dialysis Transplantation 31, suppl_1 (May 2016): i354. http://dx.doi.org/10.1093/ndt/gfw182.06.

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2

Luo, Yichen, Liang Du, Zhimeng Yao, Fan Liu, Kai Li, Feifei Li, Jianlin Zhu, et al. "Generation and Application of Inducible Chimeric RNA ASTN2-PAPPAas Knockin Mouse Model." Cells 11, no. 2 (January 14, 2022): 277. http://dx.doi.org/10.3390/cells11020277.

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Chimeric RNAs (chiRNAs) play many previously unrecognized roles in different diseases including cancer. They can not only be used as biomarkers for diagnosis and prognosis of various diseases but also serve as potential therapeutic targets. In order to better understand the roles of chiRNAs in pathogenesis, we inserted human sequences into mouse genome and established a knockin mouse model of the tamoxifen-inducible expression of ASTN2-PAPPA antisense chimeric RNA (A-PaschiRNA). Mice carrying the A-PaschiRNA knockin gene do not display any apparent abnormalities in growth, fertility, histological, hematopoietic, and biochemical indices. Using this model, we dissected the role of A-PaschiRNA in chemical carcinogen 4-nitroquinoline 1-oxide (4NQO)-induced carcinogenesis of esophageal squamous cell carcinoma (ESCC). To our knowledge, we are the first to generate a chiRNA knockin mouse model using the Cre-loxP system. The model could be used to explore the roles of chiRNA in pathogenesis and potential targeted therapies.

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3

de Winter, J., M. Yuen, R. Van der Pijl, F. Li, S. Shengyi, S. Conijn, M. Van de Locht, et al. "P.162Novel Kbtbd13R408C-knockin mouse model phenocopies NEM6 myopathy." Neuromuscular Disorders 29 (October 2019): S95. http://dx.doi.org/10.1016/j.nmd.2019.06.217.

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4

Wegener, Eike, Cornelia Brendel, Andre Fischer, Swen Hülsmann, Jutta Gärtner, and Peter Huppke. "Characterization of the MeCP2R168X Knockin Mouse Model for Rett Syndrome." PLoS ONE 9, no. 12 (December 26, 2014): e115444. http://dx.doi.org/10.1371/journal.pone.0115444.

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5

Rose, Samuel J., Lisa H. Kriener, Ann K. Heinzer, Xueliang Fan, Robert S. Raike, Arn M. J. M. van den Maagdenberg, and Ellen J. Hess. "The first knockin mouse model of episodic ataxia type 2." Experimental Neurology 261 (November 2014): 553–62. http://dx.doi.org/10.1016/j.expneurol.2014.08.001.

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6

Sundberg, J. P., C. H. Pratt, K. A. Silva, V. E. Kennedy, L. Goodwin, W. Qin, and A. Bowcock. "394 Card14 knockin mouse model of psoriasis and psoriatic arthritis." Journal of Investigative Dermatology 136, no. 5 (May 2016): S70. http://dx.doi.org/10.1016/j.jid.2016.02.428.

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7

Baelde, R., A. Fortes Monteiro, E. Nollet, R. Galli, J. Strom, J. van der Velden, C. Ottenheijm, and J. de Winter. "P400 Kbtbd13R408C-knockin mouse model elucidates mitochondrial pathomechanism in NEM6." Neuromuscular Disorders 33 (October 2023): S123. http://dx.doi.org/10.1016/j.nmd.2023.07.231.

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8

Yuan, Weiming, Xiangshu Wen, Ping Rao, Seil Kim, and Peter Cresswell. "Characterization of a human CD1d-knockin mouse (106.44)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 106.44. http://dx.doi.org/10.4049/jimmunol.188.supp.106.44.

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Abstract CD1d-restricted natural killer T (NKT) cells regulate the immune system in response to a broad range of diseases. The CD1d/NKT antigen presentation pathway is largely conserved between human and mouse, however, there is distinct difference between the two species. To better study human CD1d antigen presentation in an in vivo setting, we have generated a human CD1d knock-in (KI) mouse. We have expressed human CD1d (hCD1d) in place of mouse CD1d (mCD1d). The expression of hCD1d was verified on CD4+CD8+DP thymocytes and thymic dendritic cells, which are involved in NKT cell positive and negative selections, respectively, in thymus. CD1d-α-GalCer tetramer+ invariant NKT (iNKT) cells have been shown in thymus, spleen and liver. However, reduced numbers of iNKT cells were observed in these organs compared to that in wild-type mice. Among these iNKT cells, Vβ8 has been over-represented comparing with wild-type mouse, suggesting hCD1d preferentially selects for mouse Vβ8 chain, which is highly homologous to human Vβ11 chain. In vitro presentation of various glycolipids by BMDCs from hCD1d KI mice showed that hCD1d is functional in presenting different groups of lipids. Furthermore, lipid administration in the KI mice showed that in vivo hCD1d-restricted NKT cells are functional. In summary, our hCD1d KI mouse can be a novel model for in vivo studying hCD1d-specific antigen presentation in antitumor and antimicrobial immunity as well as autoimmune diseases.

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9

Guo, Qinxi, Hui Zheng, and Nicholas John Justice. "Central CRF system perturbation in an Alzheimer's disease knockin mouse model." Neurobiology of Aging 33, no. 11 (November 2012): 2678–91. http://dx.doi.org/10.1016/j.neurobiolaging.2012.01.002.

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10

Nomura, Naohiro, Masato Tajima, Noriko Sugawara, Tetsuji Morimoto, Yoshiaki Kondo, Mayuko Ohno, Keiko Uchida, et al. "Generation and analyses of R8L barttin knockin mouse." American Journal of Physiology-Renal Physiology 301, no. 2 (August 2011): F297—F307. http://dx.doi.org/10.1152/ajprenal.00604.2010.

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Barttin, a gene product of BSND, is one of four genes responsible for Bartter syndrome. Coexpression of barttin with ClC-K chloride channels dramatically induces the expression of ClC-K current via insertion of ClC-K-barttin complexes into plasma membranes. We previously showed that stably expressed R8L barttin, a disease-causing missense mutant, is retained in the endoplasmic reticulum (ER) of Madin-Darby canine kidney (MDCK) cells, with the barttin β-subunit remaining bound to ClC-K α-subunits (Hayama A, Rai T, Sasaki S, Uchida S. Histochem Cell Biol 119: 485–493, 2003). However, transient expression of R8L barttin in MDCK cells was reported to impair ClC-K channel function without affecting its subcellular localization. To investigate the pathogenesis in vivo, we generated a knockin mouse model of Bartter syndrome that carries the R8L mutation. These mice display disease-like phenotypes (hypokalemia, metabolic alkalosis, and decreased NaCl reabsorption in distal tubules) under a low-salt diet. Immunofluorescence and immunoelectron microscopy revealed that the plasma membrane localization of both R8L barttin and the ClC-K channel was impaired in these mice, and transepithelial chloride transport in the thin ascending limb of Henle's loop (tAL) as well as thiazide-sensitive chloride clearance were significantly reduced. This reduction in transepithelial chloride transport in tAL, which is totally dependent on ClC-K1/barttin, correlated well with the reduction in the amount of R8L barttin localized to plasma membranes. These results suggest that the major cause of Bartter syndrome type IV caused by R8L barttin mutation is its aberrant intracellular localization.

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11

Hammersen, Johanna, Jin Hou, Stephanie Wünsche, Sven Brenner, Thomas Winkler, and Holm Schneider. "A new mouse model of junctional epidermolysis bullosa: the LAMB3 628G>A knockin mouse." Molecular and Cellular Pediatrics 1, Suppl 1 (2014): A12. http://dx.doi.org/10.1186/2194-7791-1-s1-a12.

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12

Hammersen, Johanna, Jin Hou, Stephanie Wünsche, Sven Brenner, Thomas Winkler, and Holm Schneider. "A New Mouse Model of Junctional Epidermolysis Bullosa: The LAMB3 628G>A Knockin Mouse." Journal of Investigative Dermatology 135, no. 3 (March 2015): 921–24. http://dx.doi.org/10.1038/jid.2014.466.

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13

Yan, Dongqing, Robert E. Hutchison, and Golam Mohi. "Critical requirement for Stat5 in a mouse model of polycythemia vera." Blood 119, no. 15 (April 12, 2012): 3539–49. http://dx.doi.org/10.1182/blood-2011-03-345215.

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The JAK2V617F mutation has been identified in most cases of Ph-negative myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Expression of JAK2V617F results in constitutive activation of multiple signaling molecules/pathways. However, the key signaling downstream of JAK2V617F required for transformation and induction of MPNs remains elusive. Using a mouse genetic strategy, we show here that Stat5 is absolutely required for the pathogenesis of PV induced by Jak2V617F. Whereas expression of Jak2V617F in mice resulted in all the features of human PV, including an increase in red blood cells, hemoglobin, hematocrit, white blood cells, platelets, and splenomegaly, deletion of Stat5 in the Jak2V617F knockin mice normalized all the blood parameters and the spleen size. Furthermore, deletion of Stat5 completely abrogated erythropoietin (Epo)–independent erythroid colony formation evoked by Jak2V617F, a hallmark feature of PV. Re-expression of Stat5 in Stat5-deficient Jak2V617F knockin mice completely rescued the defects in transformation of hematopoietic progenitors and the PV phenotype. Together, these results indicate a critical function for Stat5 in the pathogenesis of PV. These findings also provide strong support for the development of Stat5 inhibitors as targeted therapies for the treatment of PV and other JAK2V617F-positive MPNs.

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14

Ellegood, Jacob, Jason P. Lerch, and R. Mark Henkelman. "Brain abnormalities in a Neuroligin3 R451C knockin mouse model associated with autism." Autism Research 4, no. 5 (August 31, 2011): 368–76. http://dx.doi.org/10.1002/aur.215.

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15

Gilley, Jonathan, Robert Adalbert, and Michael P. Coleman. "Modelling early responses to neurodegenerative mutations in mice." Biochemical Society Transactions 39, no. 4 (July 20, 2011): 933–38. http://dx.doi.org/10.1042/bst0390933.

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Considering the many differences between mice and humans, it is perhaps surprising how well mice model late-onset human neurodegenerative disease. Models of Alzheimer's disease, frontotemporal dementia, Parkinson's disease and Huntington's disease show some striking similarities to the corresponding human pathologies in terms of axonal transport disruption, protein aggregation, synapse loss and some behavioural phenotypes. However, there are also major differences. To extrapolate from mouse models to human disease, we need to understand how these differences relate to intrinsic limitations of the mouse system and to the effects of transgene overexpression. In the present paper, we use examples from an amyloid-overexpression model and a mutant-tau-knockin model to illustrate what we learn from each type of approach and what the limitations are. Finally, we discuss the further contributions that knockin and similar approaches can make to understanding pathogenesis and how best to model disorders of aging in a short-lived mammal.

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16

Ohno, Shinji, Nobuyuki Ono, Fumio Seki, Makoto Takeda, Shinobu Kura, Teruhisa Tsuzuki, and Yusuke Yanagi. "Measles Virus Infection of SLAM (CD150) Knockin Mice Reproduces Tropism and Immunosuppression in Human Infection." Journal of Virology 81, no. 4 (November 29, 2006): 1650–59. http://dx.doi.org/10.1128/jvi.02134-06.

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ABSTRACT The human signaling lymphocyte activation molecule (SLAM, also called CD150), a regulator of antigen-driven T-cell responses and macrophage functions, acts as a cellular receptor for measles virus (MV), and its V domain is necessary and sufficient for receptor function. We report here the generation of SLAM knockin mice in which the V domain of mouse SLAM was replaced by that of human SLAM. The chimeric SLAM had an expected distribution and normal function in the knockin mice. Splenocytes from the SLAM knockin mice permitted the in vitro growth of a virulent MV strain but not that of the Edmonston vaccine strain. Unlike in vitro infection, MV could grow only in SLAM knockin mice that also lacked the type I interferon receptor (IFNAR). After intraperitoneal or intranasal inoculation, MV was detected in the spleen and lymph nodes throughout the body but not in the thymus. Notably, the virus appeared first in the mediastinal lymph node after intranasal inoculation. Splenocytes from MV-infected IFNAR−/− SLAM knockin mice showed suppression of proliferative responses to concanavalin A. Thus, MV infection of SLAM knockin mice reproduces lymphotropism and immunosuppression in human infection, serving as a useful small animal model for measles.

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17

van den Maagdenberg, Arn M. J. M., Daniela Pietrobon, Tommaso Pizzorusso, Simon Kaja, Ludo A. M. Broos, Tiziana Cesetti, Rob C. G. van de Ven, et al. "A Cacna1a Knockin Migraine Mouse Model with Increased Susceptibility to Cortical Spreading Depression." Neuron 41, no. 5 (March 2004): 701–10. http://dx.doi.org/10.1016/s0896-6273(04)00085-6.

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18

Qin, Mei, Tianjian Huang, Zhonghua Liu, Michael Kader, Thomas Burlin, Zengyan Xia, Zachary Zeidler, Renate K. Hukema, and Carolyn B. Smith. "Cerebral Protein Synthesis in a Knockin Mouse Model of the Fragile X Premutation." ASN Neuro 6, no. 5 (September 19, 2014): 175909141455195. http://dx.doi.org/10.1177/1759091414551957.

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19

Wu, Fenfen, Wentao Mi, Dennis K. Burns, Yu Fu, Hillery F. Gray, Arie F. Struyk, and Stephen C. Cannon. "A sodium channel knockin mutant (NaV1.4-R669H) mouse model of hypokalemic periodic paralysis." Journal of Clinical Investigation 121, no. 10 (October 3, 2011): 4082–94. http://dx.doi.org/10.1172/jci57398.

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20

Turnes, Bruna, Leo Mejia, Carl Nist-Lund, Nathaniel Hodgson, Nick Andrews, Alan Kopin, and Michela Fagiolini. "NEWLY DEVELOPED TECPR2 KNOCKIN MOUSE MODEL FOR THE STUDY OF TECPR2-RELATED DISORDER." IBRO Neuroscience Reports 15 (October 2023): S145. http://dx.doi.org/10.1016/j.ibneur.2023.08.189.

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21

Nirala, Bikesh Kumar, Lyazat Kurenbekova, Tajhal Patel, Ryan Lane Shuck, Atreyi Dasgupta, Nino Carlo Rainusso, and Jason T. Yustein. "Abstract 6713: Myc-regulated miR17, 20a modulate RANK expression in osteosarcoma." Cancer Research 83, no. 7_Supplement (April 4, 2023): 6713. http://dx.doi.org/10.1158/1538-7445.am2023-6713.

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Abstract Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Approximately 25-30% of these tumors carry amplification of chromosome 8q24, which harbors the oncogene c-Myc, and correlates with a poor prognosis in patients with OS. To understand the mechanisms that underlie the ability of Myc to alter both the tumor and its surrounding tumor immune microenvironment (TiME), we generated and molecularly characterized an osteoblast-specific Cre-Lox-Stop-Lox;(LSL)-c-MycT58A;p53f/+ knockin genetically engineered mouse model (GEMM). Phenotypically, the Myc knockin-GEMM had rapid tumor development with a high incidence of metastasis. Myc-dependent gene signature in our murine model demonstrated significant homology to the human Myc-amplified OS.Interestingly, we noticed a significant reduction in the osteoclast (OCL) cell population in the Myc knockin OS tumor compared to the p53-driven. We found the expression of RANK was significantly downregulated in the Myc knockin tumor compared to the Non-knockin p53 heterozygous tumors. The RANK/RANKL pathway is vital in OCL maturation and bone modeling/remodeling. To understand the involvement of Myc in RANK regulation, we used murine-derived OS cell lines and transiently knocked down of Myc expression using siRNA. We observed a significant upregulation in RANK expression after Myc knockdown. To decipher the molecular mechanism behind the Myc-dependent regulation of RANK expression in OS, we looked into the Myc-mediated microRNAs. Myc regulates the expression of several microRNAs, including the polycistronic miR-17-92 cluster. The expression of miR17-5p and Mir20a-5p was significantly higher in the GEMM tumor tissue samples isolated from the Myc knockin compared to the p53-driven. Further, we validated the Myc-dependent regulation of miR-17-5p/20a-5p expression using transient knockdown of Myc in mouse Myc knockin-derived cell lines. To examine the role of miR17-5p/20a-5p on the RANK regulation, we performed both gain and loss-of-function studies using microRNA-17/20a mimics and inhibitors. After the treatment with miR-17-5p/20a-5p inhibitors, the expression of RANK was significantly upregulated whereas in the case of miR17/20a mimics reversed these effects and led to a downregulation of RANK expression. We established that miR-17-5p/20a-5p is causally responsible for at least part of the mechanism by which Myc regulates the RANK expression in OS.We concluded that the Myc-regulated miR17/20a modulates the RANK expression that is involved in the OCL cell population regulation and function in the OS. Citation Format: Bikesh Kumar Nirala, Lyazat Kurenbekova, Tajhal Patel, Ryan Lane Shuck, Atreyi Dasgupta, Nino Carlo Rainusso, Jason T. Yustein. Myc-regulated miR17, 20a modulate RANK expression in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6713.

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Liu, Yuning, Hong Xing, Bradley J. Wilkes, Fumiaki Yokoi, Huanxin Chen, David E. Vaillancourt, and Yuqing Li. "The abnormal firing of Purkinje cells in the knockin mouse model of DYT1 dystonia." Brain Research Bulletin 165 (December 2020): 14–22. http://dx.doi.org/10.1016/j.brainresbull.2020.09.011.

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23

Fan, Changfa, Xi Wu, Qiang Liu, Qianqian Li, Susu Liu, Jianjun Lu, Yanwei Yang, et al. "A Human DPP4-Knockin Mouse’s Susceptibility to Infection by Authentic and Pseudotyped MERS-CoV." Viruses 10, no. 9 (August 23, 2018): 448. http://dx.doi.org/10.3390/v10090448.

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Infection by the Middle East respiratory syndrome coronavirus (MERS-CoV) causes respiratory illness and has a high mortality rate (~35%). The requirement for the virus to be manipulated in a biosafety level three (BSL-3) facility has impeded development of urgently-needed antiviral agents. Here, we established anovel mouse model by inserting human dipeptidyl peptidase 4 (hDPP4) into the Rosa26 locus using CRISPR/Cas9, resulting in global expression of the transgene in a genetically stable mouse line. The mice were highly susceptible to infection by MERS-CoV clinical strain hCoV-EMC, which induced severe diffuse pulmonary disease in the animals, and could also be infected by an optimized pseudotyped MERS-CoV. Administration of the neutralizing monoclonal antibodies, H111-1 and m336, as well as a fusion inhibitor peptide, HR2P-M2, protected mice from challenge with authentic and pseudotyped MERS-CoV. These results confirmed that the hDPP4-knockin mouse is a novel model for studies of MERS-CoV pathogenesis and anti-MERS-CoV antiviral agents in BSL-3 and BSL-2facilities, respectively.

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He, Daniel. "Abstract 5092: Non-IL-2 blocking Treg-depleting anti-human CD25 mAb primes potent anti-tumor immunity and synergizes anti-tumor effects of anti-PD-1 in a novel hIL-2RA knockin model." Cancer Research 83, no. 7_Supplement (April 4, 2023): 5092. http://dx.doi.org/10.1158/1538-7445.am2023-5092.

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Abstract The therapeutic effects for cancer immunotherapy are largely hampered by intratumoral CD4+CD25+ regulatory T cells (Tregs) which leads to poor outcome in many cancer patients upon treatment of immune checkpoint inhibitors. Moreover, the balance between effector T (Teff) cells and Treg cells in the tumor microenvironment (TME) impacts on tumor progression and anti-tumor immunity. Depleting tumor-infiltrating Tregs by selectively targeting CD25 to reduce the ratios of regulatory to effector T cells (Treg/Teff) without disturbing IL-2 signalling is a promising strategy to advance anti-tumor immunity. Hence, we evaluated the in vivo anti-tumor effects of Non-IL-2 blocking Treg-depleting anti-hCD25 mAb versus IL-2-blocking anti-hCD25 mAb (Basiliximab) in an engineered hCD25 (IL-2RA) knockin mouse model.Firstly, we developed the genetically engineered CD25 (IL-2RA) humanized mouse model by ES cell targeting, in which mouse Cd25 exons 2-6 are replaced by human counterparts corresponding to the extracellular domain leaving the intracellular regions intact. Then, we performed flow cytometry analysis to confirm the surface expression of hCD25 on naive Treg cell from peripheral blood and spleen in homozygous hCD25 knockin mice. In addition, we found the hCD25 expression is upregulated on activated Treg cell derived from splenocytes for both heterozygous and homozygous hCD25 knockin mice. Furthermore, the female homozygous hCD25 knockin mice subcutaneously engrafted with MC38 syngeneic tumors received two different therapeutic anti-CD25 mAb treatment in parallel and we found the Non-IL-2 blocking Treg-depleting anti-human CD25 mAb (anti-hCD25NB) displayed more potent anti-tumor response compared to IL-2-blocking Treg-depleting anti-human CD25 mAb (anti-hCD25BL), supporting that keeping IL-2 signaling on effector T cells are required to enhance effector activation and anti-tumor immunity. Notably, the study groups treated with anti-hCD25NB plus anti-mPD-1 showed synergistic therapeutic effects as expected. As a matter of fact, both CD4+CD25+ T cells and CD4+CD25+FoxP3+ Treg cells reduced significantly upon treatment of anti-hCD25NB and anti-hCD25BL in spleen and tumors, but no big change in the number of CD4+FoxP3+ Treg cells.Likewise, anti-hCD25NB in combination with anti-mPD-1 leads to more significant CD4+CD25+ Treg depletion in spleen and tumors along with increased CD8+Granzyme B+ cytotoxic T cells.Collectively, our CD25 (IL-2RA) humanized mouse provides a powerful model to assess the in vivo preclinical therapeutic effects of CD25+ Treg-depleting antibodies for cancer immunotherapy. Citation Format: Daniel He. Non-IL-2 blocking Treg-depleting anti-human CD25 mAb primes potent anti-tumor immunity and synergizes anti-tumor effects of anti-PD-1 in a novel hIL-2RA knockin model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5092.

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Rongvaux, Anthony, Tim Willinger, Hitoshi Takizawa, Chozhavendan Rathinam, Elizabeth Eynon, Sean Stevens, Markus Manz, and Richard Flavell. "Human thrombopoietin knockin mice efficiently support human hematopoiesis in vivo (153.5)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 153.5. http://dx.doi.org/10.4049/jimmunol.186.supp.153.5.

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Abstract Hematopoietic stem cells (HSCs) both self-renew and give rise to all blood cells for the lifetime of an individual. Xenogeneic mouse models are broadly used to study human hematopoietic stem and progenitor cell biology in vivo. However, maintenance, differentiation, and function of human hematopoietic cells is suboptimal in these hosts. We hypothesized that this defect was due to reduced cross-reactivity of mouse cytokines on the human receptor. Thrombopoietin (TPO) has been demonstrated as a crucial cytokine supporting maintenance and self-renewal of HSCs. We generated RAG2-/-γc-/- mice in which we replaced the gene encoding mouse TPO by its human homologue, and we transplanted human CD34+ cells in these recipients. Homozygous humanization of TPO (TPOh/h) led to increased levels (higher than 80%) and longer maintenance (more than 6 months) of human cell engraftment in the bone marrow of the hosts. Multilineage differentiation of hematopoietic cells was also improved, with an increased ratio of myelomonocytic verus lymphoid lineages. Moreover, maintenance of human stem and progenitor cells was improved : we observed a significant increase in the fraction of human Lin-CD34+CD38-CD90+CD45RA- cells in TPOh/h compared to control recipients; and CD34+ cells purified from TPOh/h primary recipient had a significantly increased capacity to efficiently engraft secondary recipients. Therefore, RAG2-/-γc-/- TPO-humanized mice represent a novel model to study human hematopoiesis in vivo.

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Seo, Kyowon, Eun Kyoung Kim, Jaeil Choi, Dae-Seong Kim, and Jin-Hong Shin. "Functional recovery of a novel knockin mouse model of dysferlinopathy by readthrough of nonsense mutation." Molecular Therapy - Methods & Clinical Development 21 (June 2021): 702–9. http://dx.doi.org/10.1016/j.omtm.2021.04.015.

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Bonnet, Marie, Fang Huang, Touati Benoukraf, Olivier Cabaud, Christophe Verthuy, Anaelle Boucher, Sébastien Jaeger, Pierre Ferrier, and Salvatore Spicuglia. "Duality of Enhancer Functioning Mode Revealed in a Reduced TCRβ Gene Enhancer Knockin Mouse Model." Journal of Immunology 183, no. 12 (November 18, 2009): 7939–48. http://dx.doi.org/10.4049/jimmunol.0902179.

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Mohamed, Rasha M. S. M., Sachio Morimoto, Islam A. A. E. H. Ibrahim, Dong-Yun Zhan, Cheng-Kun Du, Masaki Arioka, Tatsuya Yoshihara, Fumi Takahashi-Yanaga, and Toshiyuki Sasaguri. "GSK-3β heterozygous knockout is cardioprotective in a knockin mouse model of familial dilated cardiomyopathy." American Journal of Physiology-Heart and Circulatory Physiology 310, no. 11 (June 1, 2016): H1808—H1815. http://dx.doi.org/10.1152/ajpheart.00771.2015.

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Glycogen synthase kinase-3β (GSK-3β) plays a central role in both cardiac physiology and pathology. Herein we want to clarify the role of GSK-3β in familial dilated cardiomyopathy. We generated a mouse model carrying a heterozygous knockout mutation of GSK-3β (GSK-3β+/− KO), together with a ΔK210 knockin mutation in cardiac troponin T (ΔK210 cTnT KI), which was proved to be one of the genetic causes of familial dilated cardiomyopathy (DCM). GSK-3β+/− KO prevented the slow and rapid deterioration in left ventricular systolic function accompanying heart failure (HF) in DCM mice with heterozygous and homozygous ΔK210 cTnT KI mutations, respectively. GSK-3β+/− KO also prevented cardiac enlargement, myocardial fibrosis, and cardiomyocyte apoptosis and markedly reduced the expression of cardiac β-myosin heavy chain isoform, indicative of HF, in DCM mice with homozygous ΔK210 cTnT KI mutation. GSK-3β+/− KO also extended the life span of these DCM mice. This study suggests that the inhibition of GSK-3β is cardioprotective in familial DCM associated with ΔK210 cTnT mutation.

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Yang, Sung-Sen, Tetsuji Morimoto, Tatemitsu Rai, Motoko Chiga, Eisei Sohara, Mayuko Ohno, Keiko Uchida, et al. "Molecular Pathogenesis of Pseudohypoaldosteronism Type II: Generation and Analysis of a Wnk4D561A/+ Knockin Mouse Model." Cell Metabolism 5, no. 5 (May 2007): 331–44. http://dx.doi.org/10.1016/j.cmet.2007.03.009.

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Baelde, R., V. Janssen, A. Fortes Monteiro, R. Galli, M. Methawasin, H. Granzier, D. Kuster, J. van der Velden, C. Ottenheijm, and J. de Winter. "P407 Kbtbd13R408C-knockin mouse model reveals impaired relaxation kinetics as novel pathomechanism for NEM6 cardiomyopathy." Neuromuscular Disorders 33 (October 2023): S125. http://dx.doi.org/10.1016/j.nmd.2023.07.238.

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Valenzuela, Alicia, Karen Fancher, Cat Lutz, and Stephen Rockwood. "Mouse Models for Immunology Research available from The Jackson Laboratory Repository." Journal of Immunology 198, no. 1_Supplement (May 1, 2017): 121.17. http://dx.doi.org/10.4049/jimmunol.198.supp.121.17.

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Abstract The Jackson Laboratory Repository serves as a centralized facility for the development, distribution and cryopreservation of mouse models of human biology and disease. Hundreds of new strains are added annually to one of the largest collections of characterized mouse strains available. Our newest strains carry genes associated with T lymphocyte regulation and development. T cells from the Fyb (ADAP) knockout (KO) exhibit impaired proliferation and TCR-mediated adhesion. T cells from the Cd27 KO have a diminished viral response and a delayed memory cell response. A conditional KO of Kdm6b (Jmjd3), a histone demethylase, results in altered T cell differentiation. Finally, conditional expression of an HA-tagged mutant human transcription factor, FOXO, is associated with regulatory T cell function. Mice carrying the Ifnar1 (interferon αβ receptor 1) KO allele have a reduced immune response and increased susceptibility to viral infection. The Ifnar1 KO, combined with the Ifngr1 (interferon γ receptor 1) KO allele provide a model for Zika virus (and other viruses) pathogenesis. New tool strains include two conditional GFP knockin reporters, one in Spic, a transcription factor expressed in macrophages, and the second in Ebf1, a transcription factor involved in B cell development. A knockin to Zbtb46, a zinc finger transcription factor, expresses Cre recombinase in classical dendritic cells. Donating a strain to the Repository fulfills the NIH’s requirements for sharing mice. Researchers wishing to have strains considered for inclusion in the Repository are encouraged to submit their strains: www.jax.org/donate-a-mouse. This work is supported by NIH, HHMI, and several private charitable foundations.

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Zhao, Ling, Lemlem Alemu, Jun Cheng, Tao Zhen, Alan D. Friedman, and Pu Paul Liu. "Functional Dissection of the C Terminus of CBFβ-SMMHC Indicates a Critical Role of the Multimerization Domain during Hematopoiesis and Leukemogenesis." Blood 124, no. 21 (December 6, 2014): 2218. http://dx.doi.org/10.1182/blood.v124.21.2218.2218.

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Abstract The recurrent chromosome 16 inversion (inv(16)) in acute myeloid leukemia (AML) subtype M4Eo results in a fusion between CBFB and MYH11 genes, which encodes a chimeric protein CBFβ-SMMHC (core binding factor β - smooth muscle myosin heavy chain). We previously generated mouse CBFB-MYH11 knock-in models that mimic the human inv(16) AML and demonstrated that the CBFβ-SMMHC fusion protein blocks RUNX1 and CBFβ function during definitive hematopoiesis and plays a driving role in leukemogenesis. Our recent studies indicated that the C-terminus of CBFβ-SMMHC, which contains domains for multimerization and transcriptional repression, is important for leukemogenesis by CBFβ-SMMHC (Kamikubo et al, Blood 121:638, 2013). In this study we generated a new CBFB-MYH11 knock-in mouse model to determine the role of the multimerization domain of CBFβ-SMMHC during hematopoiesis and leukemogenesis. Previous studies have dissected the assembly competence domain (ACD) of the CBFβ-SMMHC C-terminus to identify the critical amino acid residuals for multimerization (Zhang et al., Oncogene 25:7289, 2006). Among them, mutations in helices D and E are the ones that affect multimerization the most. Importantly, the helices D and E mutations do not interfere with the repression function of CBFβ-SMMHC. Therefore, we generated knock-in mice expressing CBFβ-SMMHC with mutated helices D &E in the ACD of the C-terminus (mDE) to determine the role of multimerization for the in vivo function of CBFβ-SMMHC. The embryonic hematopoietic phenotype in the mDE knockin embryos is very similar to what we have observed in the knockin embryos expressing C-terminally-deleted CBFβ-SMMHC (Kamikubo et al, Blood 121:638, 2013), i.e., heterozygous embryos (Cbfb+/mDE) were viable and showed no defects in fetal liver definitive hematopoiesis, while homozygous embryos (CbfbmDE/mDE) showed hemorrhage in the central nervous system and died around E12.5, as seen in the full length CBFβ-SMMHC heterozygous knockin mice and the Cbfb-/- and Runx1-/- mice. Analysis of peripheral blood from adult Cbfb+/mDE mice showed decreased B cell population and increased T cell population, while the myeloid compartment was unchanged. Preliminary findings suggest that leukemogenesis is at least delayed in the Cbfb+/mDE mice as compared to mice expressing full-length CBFβ-SMMHC. Therefore the multimerization function of CBFβ-SMMHC is critical for its ability to induce defects in embryonic hematopoiesis and for leukemogenesis. Disclosures No relevant conflicts of interest to declare.

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Shimura, Daisuke, Yoichiro Kusakari, Tetsuo Sasano, Yasuhiro Nakashima, Gaku Nakai, Qibin Jiao, Meihua Jin, et al. "Heterozygous deletion of sarcolipin maintains normal cardiac function." American Journal of Physiology-Heart and Circulatory Physiology 310, no. 1 (January 1, 2016): H92—H103. http://dx.doi.org/10.1152/ajpheart.00411.2015.

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Sarcolipin (SLN) is a small proteolipid and a regulator of sarco(endo)plasmic reticulum Ca2+-ATPase. In heart tissue, SLN is exclusively expressed in the atrium. Previously, we inserted Cre recombinase into the endogenous SLN locus by homologous recombination and succeeded in generating SLN-Cre knockin (SlnCre/+) mice. This SlnCre/+ mouse can be used to generate an atrium-specific gene-targeting mutant, and it is based on the Cre-loxP system. In the present study, we used adult SlnCre/+ mice atria and analyzed the effects of heterozygous SLN deletion by Cre knockin before use as the gene targeting mouse. Both SLN mRNA and protein levels were decreased in SlnCre/+ mouse atria, but there were no morphological, physiological, or molecular biological abnormalities. The properties of contractility and Ca2+ handling were similar to wild-type (WT) mice, and expression levels of several stress markers and sarcoplasmic reticulum-related protein levels were not different between SlnCre/+ and WT mice. Moreover, there was no significant difference in sarco(endo)plasmic reticulum Ca2+-ATPase activity between the two groups. We showed that SlnCre/+ mice were not significantly different from WT mice in all aspects that were examined. The present study provides basic characteristics of SlnCre/+ mice and possibly information on the usefulness of SlnCre/+ mice as an atrium-specific gene-targeting model.

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Price, Brandee A., Ivette M. Sandoval, Fung Chan, David L. Simons, Samuel M. Wu, Theodore G. Wensel, and John H. Wilson. "Mislocalization and Degradation of Human P23H-Rhodopsin-GFP in a Knockin Mouse Model of Retinitis Pigmentosa." Investigative Opthalmology & Visual Science 52, no. 13 (December 24, 2011): 9728. http://dx.doi.org/10.1167/iovs.11-8654.

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Ludwig, Michael R., Kyoko Kojima, Gregory J. Bowersock, Dongquan Chen, Nirag C. Jhala, Donald J. Buchsbaum, William E. Grizzle, Christopher A. Klug, and James A. Mobley. "Surveying the serologic proteome in a tissue-specific kras(G12D) knockin mouse model of pancreatic cancer." PROTEOMICS 16, no. 3 (January 18, 2016): 516–31. http://dx.doi.org/10.1002/pmic.201500133.

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Li, Kun, Christine L. Wohlford-Lenane, Rudragouda Channappanavar, Jung-Eun Park, James T. Earnest, Thomas B. Bair, Amber M. Bates, et al. "Mouse-adapted MERS coronavirus causes lethal lung disease in human DPP4 knockin mice." Proceedings of the National Academy of Sciences 114, no. 15 (March 27, 2017): E3119—E3128. http://dx.doi.org/10.1073/pnas.1619109114.

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The Middle East respiratory syndrome (MERS) emerged in Saudi Arabia in 2012, caused by a zoonotically transmitted coronavirus (CoV). Over 1,900 cases have been reported to date, with ∼36% fatality rate. Lack of autopsies from MERS cases has hindered understanding of MERS-CoV pathogenesis. A small animal model that develops progressive pulmonary manifestations when infected with MERS-CoV would advance the field. As mice are restricted to infection at the level of DPP4, the MERS-CoV receptor, we generated mice with humanized exons 10–12 of the mouse Dpp4 locus. Upon inoculation with MERS-CoV, human DPP4 knockin (KI) mice supported virus replication in the lungs, but developed no illness. After 30 serial passages through the lungs of KI mice, a mouse-adapted virus emerged (MERSMA) that grew in lungs to over 100 times higher titers than the starting virus. A plaque-purified MERSMA clone caused weight loss and fatal infection. Virus antigen was observed in airway epithelia, pneumocytes, and macrophages. Pathologic findings included diffuse alveolar damage with pulmonary edema and hyaline membrane formation associated with accumulation of activated inflammatory monocyte–macrophages and neutrophils in the lungs. Relative to the parental MERS-CoV, MERSMA viruses contained 13–22 mutations, including several within the spike (S) glycoprotein gene. S-protein mutations sensitized viruses to entry-activating serine proteases and conferred more rapid entry kinetics. Recombinant MERSMA bearing mutant S proteins were more virulent than the parental virus in hDPP4 KI mice. The hDPP4 KI mouse and the MERSMA provide tools to investigate disease causes and develop new therapies.

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Santillo, Alessandra, Sara Falvo, Massimo Venditti, Anna Di Maio, Gabriella Chieffi Baccari, Francesco Errico, Alessandro Usiello, Sergio Minucci, and Maria Maddalena Di Fiore. "D-Aspartate Depletion Perturbs Steroidogenesis and Spermatogenesis in Mice." Biomolecules 13, no. 4 (March 30, 2023): 621. http://dx.doi.org/10.3390/biom13040621.

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High levels of free D-aspartate (D-Asp) are present in vertebrate testis during post-natal development, coinciding with the onset of testosterone production, which suggests that this atypical amino acid might participate in the regulation of hormone biosynthesis. To elucidate the unknown role of D-Asp on testicular function, we investigated steroidogenesis and spermatogenesis in a one-month-old knockin mouse model with the constitutive depletion of D-Asp levels due to the targeted overexpression of D-aspartate oxidase (DDO), which catalyzes the deaminative oxidation of D-Asp to generate the corresponding α-keto acid, oxaloacetate, hydrogen peroxide, and ammonium ions. In the Ddo knockin mice, we found a dramatic reduction in testicular D-Asp levels, accompanied by a significant decrease in the serum testosterone levels and testicular 17β-HSD, the enzyme involved in testosterone biosynthesis. Additionally, in the testes of these Ddo knockin mice, the expression of PCNA and SYCP3 proteins decreased, suggesting alterations in spermatogenesis-related processes, as well as an increase in the cytosolic cytochrome c protein levels and TUNEL-positive cell number, which indicate an increase in apoptosis. To further investigate the histological and morphometric testicular alterations in Ddo knockin mice, we analyzed the expression and localization of prolyl endopeptidase (PREP) and disheveled-associated activator of morphogenesis 1 (DAAM1), two proteins involved in cytoskeletal organization. Our results showed that the testicular levels of DAAM1 and PREP in Ddo knockin mice were different from those in wild-type animals, suggesting that the deficiency of D-Asp is associated with overall cytoskeletal disorganization. Our findings confirmed that physiological D-Asp influences testosterone biosynthesis and plays a crucial role in germ cell proliferation and differentiation, which are required for successful reproduction.

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Rongvaux, Anthony, Tim Willinger, Hitoshi Takizawa, Chozhavendan Rathinam, Elizabeth E. Eynon, Sean Stevens, Markus G. Manz, and Richard A. Flavell. "Human Thrombopoietin Knockin Mice Efficiently Support Human Hematopoiesis In Vivo." Blood 116, no. 21 (November 19, 2010): 403. http://dx.doi.org/10.1182/blood.v116.21.403.403.

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Abstract Abstract 403 Hematopoietic stem cells (HSCs) both self-renew and give rise to all blood cells for the lifetime of an individual. Xenogeneic mouse models are currently broadly used to experimentally study human hematopoietic stem and progenitor cell biology in vivo. However, maintenance, differentiation, and function of human hematopoietic cells are suboptimal in these hosts. More specifically, (i) human cell engraftment is only transient, not lasting for the life of recipient mice, (ii) there is an unphysiological bias towards the lymphoid lineage as well as poor differentiation of myeloid cells, and (iii) there is an important variability in the engraftment levels between different individual animals. Thrombopoietin (TPO) has been demonstrated as a crucial cytokine supporting maintenance and self-renewal of HSCs. Although TPO is mouse to human cross-reactive at supraphysiological levels, we speculated that species differences would lead to insufficient TPO activity on human cells in the xenogeneic environment. We thus generated RAG2−/−γc−/− mice in which we replaced the gene encoding mouse TPO by its human homologue. This led to the expression of human TPO at human physiological levels in the serum and tissues of TPO knockin mice. Homozygous humanization of TPO (TPOh/h) led to significantly increased levels of human engraftment in the bone marrow of the hosts (an approximately 2-fold increase). TPOh/h recipients also displayed a lower engraftment variability, with an at least 80% human chimerism in 75% of the mice, and engraftment levels were maintained for longer periods of time, up to 6–7 months, while they declined after 4 months in control recipient mice. Multilineage differentiation of hematopoietic cells was also improved, with an increased ratio between granulocytes versus and lymphocytes that better reflects the physiological human blood composition. Thus, TPOh/h recipient mice provide significant improvements compared to previously available models in all three limitations listed above. Importantly, we performed phenotypical and functional analyses of human hematopoietic stem and progenitor cells in TPOh/h compared to control recipients. We observed a significant increase in the fraction of human Lin−CD34+CD38loCD90+CD45RA− cells, a population previously identified as highly enriched in functional long-term HSC. Because serial transplantation is the most stringent protocol to functionally measure the self-renewal capacity of HSCs, we purified human CD34+ cells from TPOh/h and control primary recipients and transplanted them into secondary recipients. Human CD34+ cells isolated from control primary recipients had a very low capacity to serially engraft (with human CD45+ cells detected in only 2 of 11 secondary recipients). By contrast, CD34+ cells isolated from TPOh/h primary recipients had an increased capacity to efficiently engraft secondary recipients (with human CD45+ cells present in the bone marrow of 15 of 19 secondary recipients). This result indicates that the presence of human TPO in the primary recipient favored the maintenance of human cells with enhanced self-renewal capacity. In conclusion, we demonstrate here that RAG2−/−γc−/− TPO-humanized mice efficiently support a population of cells immunophenotypically and functionally enriched in hematopoietic stem and progenitor cells. This leads to enhanced engraftment levels, better maintenance of human chimerism and improved multilineage differentiation. Therefore, RAG2−/−γc−/− TPO-humanized mice represent a novel model to study human hematopoiesis in vivo. We anticipate that this model will be useful to study human hematopoietic stem cells in vivo, with applications in the fields of hematopoiesis, hematology and hematolo-oncology. Disclosures: Stevens: Regeneron Pharmaceuticals: Employment; AnaptysBio Inc: Employment.

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Duan, Wenming, Manal Y. Gabril, Madeleine Moussa, Franky L. Chan, Hideki Sakai, Guohua Fong, and Jim W. Xuan. "Knockin of SV40 Tag oncogene in a mouse adenocarcinoma of the prostate model demonstrates advantageous features over the transgenic model." Oncogene 24, no. 9 (January 17, 2005): 1510–24. http://dx.doi.org/10.1038/sj.onc.1208229.

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van Oort, Ralph J., Jonathan L. Respress, Na Li, Corey Reynolds, Angela C. De Almeida, Darlene G. Skapura, Leon J. De Windt, and Xander H. T. Wehrens. "Accelerated Development of Pressure Overload–Induced Cardiac Hypertrophy and Dysfunction in an RyR2-R176Q Knockin Mouse Model." Hypertension 55, no. 4 (April 2010): 932–38. http://dx.doi.org/10.1161/hypertensionaha.109.146449.

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Zhao, Baobing, Yang Mei, Ronen Sumagin, Jing Yang, Chelsea Thorsheim, Liang Zhao, Timothy J. Stalker, et al. "Pleckstrin-2 Plays an Essential Role in the Pathogenesis of JAK2V617F-Induced Myeloproliferative Neoplasms." Blood 128, no. 22 (December 2, 2016): 798. http://dx.doi.org/10.1182/blood.v128.22.798.798.

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Abstract V617F driver mutation of JAK2 is the leading cause of the Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs). Studies on the pathogenesis of JAK2V617F positive MPNs have primarily focused on deregulation of JAK2 and STAT activities. It remains unclear exactly how JAK2-STAT downstream targets are involved in the development of the MPNs. We previously reported that pleckstrin-2 (Plek2) plays an important role in terminal erythropoiesis in vitro. Here we show that Plek2 is a downstream target of the JAK2-STAT5 pathway in erythroid, megakaryocytic, and granulocytic cells. Plek2 is significantly upregulated by JAK2V617F in both transduced primary mouse hematopoietic cells and in patients with JAK2V617F positive MPNs. Using a JAK2V617F knockin mouse model, we demonstrated that loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes including reticulocytosis, thrombocytosis, neutrophilia, and splenomegaly, thereby reverting the widespread vascular occlusions and lethality of JAK2V617F knockin mice (Figure 1A). These phenotypes were also transplantable indicating the role of Plek2 in mediating the pathogenesis of JAK2V617F-induced MPNs is cell-intrinsic (Figure 1B). Our study identifies Plek2 as a novel effector of JAK2-STAT5 pathway and a key factor in the pathogenesis of JAK2V617F-induced MPNs. Figure 1. Loss of Plek2 Rescues The Lethality of JAK2V617F Knockin Mice. (A) Kaplan-Meier survival analysis of indicated mice. Both males and females were included in each group. JAK2+/+Plek2+/+mice, n=34; JAK2+/+Plek2-/-mice, n=34;JAK2VF/+Plek2+/+ mice, n=36; JAK2VF/+Plek2-/- mice, n=36. (B) Kaplan-Meier survival analysis of the transplanted mice. JAK2+/+Plek2+/+mice, n=10; JAK2+/+Plek2-/-mice, n=10;JAK2VF/+Plek2+/+ mice, n=17; JAK2VF/+Plek2-/- mice, n=17. Figure 1. Loss of Plek2 Rescues The Lethality of JAK2V617F Knockin Mice. (A) Kaplan-Meier survival analysis of indicated mice. Both males and females were included in each group. JAK2+/+Plek2+/+mice, n=34; JAK2+/+Plek2-/-mice, n=34;JAK2VF/+Plek2+/+ mice, n=36; JAK2VF/+Plek2-/- mice, n=36. (B) Kaplan-Meier survival analysis of the transplanted mice. JAK2+/+Plek2+/+mice, n=10; JAK2+/+Plek2-/-mice, n=10;JAK2VF/+Plek2+/+ mice, n=17; JAK2VF/+Plek2-/- mice, n=17. Disclosures No relevant conflicts of interest to declare.

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Kim, Caroline S., Vasily V. Vasko, Yasuhito Kato, Michael Kruhlak, Motoyasu Saji, Sheue-Yann Cheng, and Matthew D. Ringel. "AKT Activation Promotes Metastasis in a Mouse Model of Follicular Thyroid Carcinoma." Endocrinology 146, no. 10 (October 1, 2005): 4456–63. http://dx.doi.org/10.1210/en.2005-0172.

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The phosphatidylinositol 3-kinase/AKT pathway is crucial to many cell functions, and its dysregulation in tumors is a common finding. The molecular basis of follicular thyroid cancer metastasis is not well understood but may also be influenced by AKT activation. We previously created a knockin mutant mouse that expresses a mutant thyroid hormone receptor-β gene (TRβPV mouse) that spontaneously develops thyroid cancer and distant metastasis similar to human follicular thyroid cancer. In this study, we investigated whether our mouse model exhibits similar AKT activation as human follicular thyroid cancer. Western blot analysis on thyroids from both wild-type and TRβPV/PV mice revealed elevation of activated AKT in TRβPV/PV mice. Immunohistochemistry and confocal microscopy reveal activated AKT in both the thyroid and metastatic lesions of TRβPV/PV mice. Whereas all three AKT isoforms were overexpressed in primary tumors from TRβPV/PV mice in the cytoplasm of thyroid cancer cells, only AKT1 was also found in the nucleus, matching the localization of activated AKT in a pattern similar to human follicular thyroid cancer. In the metastases, all AKT isoforms correlated with phosphorylated AKT nuclear localization. We created primary thyroid cell lines derived from TRβPV/PV mice and found reduction of phosphorylated AKT levels or AKT downstream targets diminishes cell motility. Activated AKT is common to both human and mouse follicular thyroid cancer and is correlated with increased cell motility in vitro and metastasis in vivo. Thus, TRβPV/PV mice could be used to further dissect the detailed pathways underlying the progression and metastasis of follicular thyroid carcinoma.

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mora, conchi, Ainhoa Garcia, Nuria Marzo, Jordi Altirriba, Ramon Gomis, Javier Martín, and Sagrario Ortega. "Role of Cdk4 in immunological tolerance and in pancreatic beta cell mass homeostasis in T1D (99.14)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 99.14. http://dx.doi.org/10.4049/jimmunol.182.supp.99.14.

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Abstract Cdk4 plays a central role in perinatal pancreatic β cell replication and is also highly expressed in healthy, adult human pancreatic beta cells. We have previously reported that, when the hyperactive mutant form of Cdk4, Cdk4R24C replaces the wild type gene, it causes β cell hyperplasia without promoting hypoglycemia in a non-autoimmune-prone mouse strain. We found out that when the mutant Cdk4R24C knockin model is backcrossed onto the NOD genetic background, diabetes is exacerbated due to the expression of the mutated Cdk4R24C form in the NOD immune system too, as in the absence of NODCdk4R24C lymphocytes (NOD/SCID model), βcells become resistant to adoptively transferred autoimmune attack. Since the knockin model does not allow discriminating between the role of Cdk4 in either β cells or in the immune system, we have designed a model where overexpression of Cdk4 is restricted specifically to NOD β cells. We have obtained transgenic lines in the NOD genetic background in which the Rat Insulin Promoter (RIP) drives the expression of either Wild Type (WT) Cdk4 (Cdk4wt) or its mutant, hyperactive form, (Cdk4R24C), leaving the lymphocytic compartment presumably intact. This experimental approach will allow us to determine whether β cell hyperproliferation induced by Cdk4 overexpression specifically on pancreatic β cells, balances the autoimmune attack against β cells inherent to the NOD mice, and leads to an steady-state of long-lasting imunological tolerance.

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Zhao, Xiaofeng, Xu Peng, Shaogang Sun, Ann Y. J. Park, and Jun-Lin Guan. "Role of kinase-independent and -dependent functions of FAK in endothelial cell survival and barrier function during embryonic development." Journal of Cell Biology 189, no. 6 (June 7, 2010): 955–65. http://dx.doi.org/10.1083/jcb.200912094.

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Focal adhesion kinase (FAK) is essential for vascular development as endothelial cell (EC)–specific knockout of FAK (conditional FAK knockout [CFKO] mice) leads to embryonic lethality. In this study, we report the differential kinase-independent and -dependent functions of FAK in vascular development by creating and analyzing an EC-specific FAK kinase-defective (KD) mutant knockin (conditional FAK knockin [CFKI]) mouse model. CFKI embryos showed apparently normal development through embryonic day (E) 13.5, whereas the majority of CFKO embryos died at the same stage. Expression of KD FAK reversed increased EC apoptosis observed with FAK deletion in embryos and in vitro through suppression of up-regulated p21. However, vessel dilation and defective angiogenesis of CFKO embryos were not rescued in CFKI embryos. ECs without FAK or expressing KD FAK showed increased permeability, abnormal distribution of vascular endothelial cadherin (VE-cadherin), and reduced VE-cadherin Y658 phosphorylation. Together, our data suggest that kinase-independent functions of FAK can support EC survival in vascular development through E13.5 but are insufficient for maintaining EC function to allow for completion of embryogenesis.

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Datta, Nabanita S., Tareq A. Samra, and Abdul B. Abou-Samra. "Parathyroid hormone induces bone formation in phosphorylation-deficient PTHR1 knockin mice." American Journal of Physiology-Endocrinology and Metabolism 302, no. 10 (May 15, 2012): E1183—E1188. http://dx.doi.org/10.1152/ajpendo.00380.2011.

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Activation of G protein-coupled receptors by agonists leads to receptor phosphorylation, internalization of ligand receptor complexes, and desensitization of hormonal response. The role of parathyroid hormone (PTH) receptor 1, PTHR1, is well characterized and known to regulate cellular responsiveness in vitro. However, the role of PTHR1 phosphorylation in bone formation is yet to be investigated. We have previously demonstrated that impaired internalization and sustained cAMP stimulation of phosphorylation-deficient (PD) PTHR1 leads to exaggerated cAMP response to subcutaneous PTH infusion in a PD knockin mouse model. To understand the physiological role of receptor internalization on PTH bone anabolic action, we examined bone parameters of wild-type (WT) and PD knockin female and male mice following PTH treatment. We found a decrease in total and diaphyseal bone mineral density in female but not in male PD mice compared with WT controls at 3–6 mo of age. This effect was attenuated at older age groups. PTH administration displayed increased bone volume and trabecular thickness in the vertebrae and distal femora of both WT and PD animals. These results suggest that PTHR1 phosphorylation does not play a major role in the anabolic action of PTH.

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Volta, Mattia, and Heather Melrose. "LRRK2 mouse models: dissecting the behavior, striatal neurochemistry and neurophysiology of PD pathogenesis." Biochemical Society Transactions 45, no. 1 (February 8, 2017): 113–22. http://dx.doi.org/10.1042/bst20160238.

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Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of familial Parkinson's disease (PD), resembling the sporadic disorder. Intensive effort has been directed toward LRRK2 mouse modeling and investigation, aimed at reproducing the human disease to inform mechanistic studies of pathogenesis and design of neuroprotective therapies. The physiological function of LRRK2 is still under exploration, but a clear role in striatal neurophysiology and animal behavior has emerged. Alterations in LRRK2 impair dopamine (DA) transmission, regulation and signaling, in addition to corticostriatal synaptic plasticity. Consistently, several subtle abnormalities in motor and nonmotor abilities have been demonstrated in LRRK2 genetic mouse models, generally paralleling preclinical symptoms of early DA dysfunction. However, the variability in model design and phenotypes observed requires a critical approach in interpreting the results, adapting the model used to the specific research question. Etiologically appropriate knockin mice might represent the ultimate animal model in which to study early disease mechanisms and therapies as well as to investigate drug effectiveness and off-target consequences.

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Unno, T., M. Wakamori, M. Koike, Y. Uchiyama, K. Ishikawa, H. Kubota, T. Yoshida, et al. "Development of Purkinje cell degeneration in a knockin mouse model reveals lysosomal involvement in the pathogenesis of SCA6." Proceedings of the National Academy of Sciences 109, no. 43 (October 10, 2012): 17693–98. http://dx.doi.org/10.1073/pnas.1212786109.

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Zhao, L., H. Alkadi, E. M. Kwon, T. Zhen, J. Lichtenberg, L. Alemu, J. Cheng, A. D. Friedman, and P. P. Liu. "The C-terminal multimerization domain is essential for leukemia development by CBFβ-SMMHC in a mouse knockin model." Leukemia 31, no. 12 (August 18, 2017): 2841–44. http://dx.doi.org/10.1038/leu.2017.262.

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Deng, Yun-Ping, and Anton Reiner. "Cholinergic interneurons in the Q140 knockin mouse model of Huntington's disease: Reductions in dendritic branching and thalamostriatal input." Journal of Comparative Neurology 524, no. 17 (June 6, 2016): 3518–29. http://dx.doi.org/10.1002/cne.24013.

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Charbonneau, Noe L., Elise C. Manalo, Sara F. Tufa, Eric J. Carlson, Valerie M. Carlberg, Douglas R. Keene, and Lynn Y. Sakai. "Fibrillin‐1 in the Vasculature: In Vivo Accumulation of eGFP‐Tagged Fibrillin‐1 in a Knockin Mouse Model." Anatomical Record 303, no. 6 (July 13, 2019): 1590–603. http://dx.doi.org/10.1002/ar.24217.

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