Of mice and models: improved animal models for biomedical research

Bockamp, Ernesto; Maringer, Marko; Spangenberg, Christian; Fees, Stephan; Fraser, Stuart; Eshkind, Leonid; Oesch, Franz; Zabel, Bernhard

doi:10.1152/physiolgenomics.00067.2002

Cited by 147 publications

(115 citation statements)

References 168 publications

(133 reference statements)

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“…5,[16][17][18][19][20] In the future, this approach could be combined with an inducible system (e.g., Tet on/off) to enable transient hIL-6 expression only during the regenerative phase. 51 Alternatively, hIL-6 delivery by encapsulated and therefore removable cells 52 might represent a promising therapeutic concept to promote axon regeneration upon nerve injuries in human patients. In addition to its potential therapeutic use, hIL-6 application also offers advantages for future regenerative research.…”

Section: Discussionmentioning

confidence: 99%

Boosting Central Nervous System Axon Regeneration by Circumventing Limitations of Natural Cytokine Signaling

et al. 2016

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Retinal ganglion cells (RGCs) do not normally regenerate injured axons, but die upon axotomy. Although IL-6-like cytokines are reportedly neuroprotective and promote optic nerve regeneration, their overall regenerative effects remain rather moderate. Here, we hypothesized that direct activation of the gp130 receptor by the designer cytokine hyper-IL-6 (hIL-6) might induce stronger RGC regeneration than natural cytokines. Indeed, hIL-6 stimulated neurite growth of adult cultured RGCs with significantly higher efficacy than CNTF or IL-6. This neurite growth promoting effect could be attributed to stronger activation of the JAK/STAT3 and PI3K/AKT/mTOR signaling pathways and was also observed in peripheral dorsal root ganglion neurons. Moreover, hIL-6 abrogated axon growth inhibition by central nervous system (CNS) myelin. Remarkably, continuous hIL-6 expression upon RGC-specific AAV transduction after optic nerve crush exerted stronger axon regeneration than other known regeneration promoting treatments such as lens injury and PTEN knockout, with some axons growing through the optic chiasm 6 weeks after optic nerve injury. Combination of hIL-6 with RGC-specific PTEN knockout further enhanced optic nerve regeneration. Therefore, direct activation of gp130 signaling might be a novel, clinically applicable approach for robust CNS repair.

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Section: Discussionmentioning

confidence: 99%

Boosting Central Nervous System Axon Regeneration by Circumventing Limitations of Natural Cytokine Signaling

et al. 2016

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“…Although these results are insightful, the approach has several intrinsic disadvantages, most notably the unrestricted expression pattern of the mutated gene. Consequently, several methods were developed for conditional or inducible in vivo gene expression, the details of which are described in several noteworthy reviews (Muller, 1999;Testa and Stewart, 2000;Ryding et al, 2001;Yu and Bradley, 2001;Bockamp et al, 2002;van der Weyden et al, 2002).…”

Section: Knock-in Modelsmentioning

confidence: 99%

Review: genetic models of acute myeloid leukaemia

2008

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The use of genetically engineered mice (GEM) have been critical in understanding disease states such as cancer, and none more so than acute myelogenous leukaemia (AML), a disease characterized by over 100 distinct chromosomal translocations. A substantial proportion of cases exhibiting recurrent reciprocal translocations at diagnosis, such as t(8;21) or t(15;17) have been exhaustively studied and are currently employed in clinical diagnosis. However, a definitive conclusion regarding the leukaemogenic potential of defined transgenes for this disease remains elusive. While it is increasingly apparent that a number of cooperating mutations are necessary to develop a leukaemic phenotype, the number of models reflecting these synergisms remains few. Furthermore, little emphasis has been paid to the effect of chromosomal translocations other than recurrent genetic abnormalities, with no models reflecting the multiple abnormalities observed in high-risk cases of AML accounting for 8-10% of adult AML. Here we review the differing technologies employed in generation of GEM of AML. We discuss the relevance of GEM AML from embryonic stem cell-mediated (for example retinoic acid receptor-a fusions and AML1/ETO) models; through to the valuable retroviral-mediated gene transfer models. The latter have been used to great effect in defining the transforming properties of chromosomal translocation products such as MLL (found in 5-6% of all AML cases) and NUP98 (denoting poor prognosis in therapy-related disease) and particularly when co-transduced with bad prognostic factors such as Flt3 mutations. Finally, we comment on the emergence of newer transduction technologies, which can regulate the level of expression to defined cell lineages in both primary murine and human xenografts, and discuss how combining multiple genetic modalities, more relevant models of this complex disease are being generated.

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“…Conse- Table 4 Distribution of translocation-generated oncogenes and associated models FAB classification (% of human cases) 4,109 Translocations (% of human cases) 4,109 Genes involved Transgenic models Review: Animal models of AML E Mc Cormack et al quently, several methods were developed for conditional or inducible in vivo gene expression, the details of which are described in several noteworthy reviews. [420][421][422][423][424][425] A modification of the knockin approach targets mutated genes into loci other than that of the involved gene and whose expression is restricted to the cell type where the aberrant gene is expressed in the human disease. Employing this methodology, a knockin model of PML/RARa t(15;17) using the endogenous murine cathepsin G-promoter was generated with 90% incidence of APML in comparison to only 15-20% prevalence observed in the relative hCG-PML/RARa model with similar pathology.…”

Section: Knockin Micementioning

confidence: 99%

Animal models of acute myelogenous leukaemia – development, application and future perspectives

2005

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From the early inception of the transplant models through to contemporary genetic and xenograft models, evolution of murine leukaemic model systems have been critical to our general comprehension and treatment of cancer, and, more specifically, disease states such as acute myelogenous leukaemia (AML). However, even with modern advances in therapeutics and molecular diagnostics, the majority of AML patients die from their disease. Thus, in the absence of definitive in vitro models which precisely recapitulate the in vivo setting of human AMLs and failure of significant numbers of new drugs late in clinical trials, it is essential that murine AML models are developed to exploit more specific, targeted therapeutics. While various model systems are described and discussed in the literature from initial transplant models such as BNML and spontaneous murine leukaemia virus models, to the more definitive genetic and clinically significant NOD/SCID xenograft models, there exists no single compendium which directly assesses, reviews or compares the relevance of these models. Thus, the function of this article is to provide clinicians and experimentalists a chronological, comprehensive appraisal of all AML model systems, critical discussion on the elucidation of their roles in our understanding of AML and consideration to their efficacy in the development of AML chemotherapeutics.

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Of mice and models: improved animal models for biomedical research

Cited by 147 publications

References 168 publications

Boosting Central Nervous System Axon Regeneration by Circumventing Limitations of Natural Cytokine Signaling

Boosting Central Nervous System Axon Regeneration by Circumventing Limitations of Natural Cytokine Signaling

Review: genetic models of acute myeloid leukaemia

Animal models of acute myelogenous leukaemia – development, application and future perspectives

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