Intro to the chakragati (ckr)mouse model

Introduction (download full info from http://www.cercainsights.com/downloads/Brochure.pdf)

The chakragati (ckr) mouse is a unique disease model of psychosis – the best model available for screening antipsychotic compounds. The ckr mouse has been proposed as a model of aspects of schizophrenia. The mice, created serendipitously as a result of a transgenic insertional mutation, exhibit spontaneous circling, hyperactivity, reduced social interactions, enlarged lateral ventricles, deficits in pre-pulse inhibition of acoustic startle and deficits in latent inhibition of conditioned learning. The ckr model is a US-patented transgenic mouse model of dopamine dysfunction. Cerca Insights (formerly Chakra Biotech Sdn Bhd) has an exclusive license for compound screening and offers a range of insightful screens predicting the clinical properties of discovery stage compounds using the ckr mouse.

Studies are underway on cognitive behavioral endpoints that map to the cognitive domains in the MATRICS initiative.

Development
The ckr mouse was the result of insertional mutagenesis discovered during the course of making transgenics with the mouse renin gene. Of the 19 founders with the transgene, only one did not express the transgene and when this was bred to homozygousity, it exhibited an abnormal circling behavior in response to environmental stress cues such as cage banging. The heterozygous littermates did not exhibit this circling phenotype, which has co-segregated with the transgene insertion site since its discovery in 1988. A US Patent was granted for the chakragati mouse (USPTO5,723,719) - the second transgenic animal patent.

Face Validity
Extensive research has been carried out on the ckr mouse since its discovery. The following table lists the endophenotypes reported in published literature for the ckr mouse and its mapping to clinical manifestations of psychotic disorders in humans.


Predictive Validity
The ckr mouse has been shown to have predictive validity in psychosis and cognition.
Both the typical antipyshcotics, haloperidol and pimozide, and the atypical antipsychotics, clozapine, olanzapine, risperidone, ziprasidone and quetiapine, investigated suppressed the elevated hyperactivity of the ckr mouse in a dose-dependent manner (Antipsychotic drugs dose-dependently suppress the spontaneous hyperactivity of the chakragati mouse, Neuroscience 171 (2010) 162–172) The ckr mouse exhibits deficits in pre-pulse inhibition and latent inhibition that were reversed by clozapine but not haloperidol or risperidone.

Benefits
The ckr mouse offers numerous advantages over the commonly use pharmacologically induced models used for the majority of antipsychotic screening:
- Disease model with several endophenotypes relevant to psychosis allowing simple, clear and sensitive translational outputs
- Not hypothesis biased – results independent of mechanism of action of compound
- Not confounded by the pharmacological kinetics of the inducing agent and can differentiate behavioural kinetics of comparative compounds.

The ckr model gives translational insights into the clinical features of discovery stage antipsychotic compounds.

For more information on the ckr screens available at Cerca Insights mouse please contact anthony.bishop@cercainsights.com or see our website at www.cercainsights.com


Published papers on the ckr mouse:
Ratty, A.K., Fitzgerald, L.W., Titeler, M., Glick, S.D., Mullins, J.J. & Gross, K.W. (1990) Circling behavior exhibited by a transgenic insertional mutant. Mol. Brain Res. 8: 355-358.
Fitzgerald, L.W., Ratty, A.K., Miller, K., Ellsworth, M.K., Glick, S.D. & Gross, K.W. (1991) The ontogeny of hyperactivity and circling behavior in a transgenic insertional mouse mutant. Behavioral Neuroscience 105: 753-761.
Ratty, A.K., Matsuda, Y., Elliott, R., Chapman, V. & Gross, K. (1992) Genetic mapping of two DNA markers, D16Ros1 and D16Ros2, flanking the mutation site in the chakragati mouse, a transgenic insertional mutant. Mammalian Genome 3: 5-10.
Ratty, A.K., Eddy, R., Shows, T.B. & Gross, K. (1992) Mapping of the mouse anonymous DNA fragment, D16Ros2, to human chromosome 3. Mammalian Genome 3: 46-47.
Fitzgerald, L.W., Miller, K., Ratty, A.K., Glick, S.D., Titeler, M. & Gross, K.W. (1992) Asymmetric elevation of striatal dopamine D2 receptors in the chakragati mouse: Neurobehavioral dysfunction in a transgenic insertional mutant. Brain Research 580: 18-26.
Fitzgerald, L.W., Ratty, A.K., Titeler, M., Gross, K.W. & Glick, S.D. (1993) Specificity of behavioral and neurochemical dysfunction in the chakragati mouse: A novel genetic model of a movement disorder. Brain Research, 608: 247-258.
Ratty, A.K., Gross, K.W., Fitzgerald, L.W. & Glick, S.D. (1994) The chakragati mouse: A model for brain dopaminergic dysfunction In Dopamine Receptors and Transporters (H.B. Niznik, ed) pp 493-509, Marcel Dekker, Inc.
Smiraglia, D.J., Ratty, A.K. and Gross, K.W. (1997) Physical characterisation of the chromosomal rearrangements that accompany the transgene insertion in the chakragati mouse mutant. Genomics 45:562-571.
Smiraglia, D.J., Wu, C, Ellsworth, M.K., Ratty, A.K., Chapman, V.M. and Gross, K.W. (1997) Genetic characterisation of the chromosomal rearrangments that accompany the transgene insertion in the chakragati mouse mutant. Genomics 45: 572-579.
Torres, G., Hallas, B.H., Vernace, V.A., Jones, C., Gross, K.W. and Horowitz, J.M. (2004) A neurobehavioural screening of the ckr mouse mutant: implications for an animal model of schizophrenia. Brain Res. Bull., 62: 315-326
Torres, G., Meeder, B.A., Hallas, B.H., Spernyak, J.A., Mazurchuk, R., Jones, C.A., Gross, K. W. and Horowitz, J.M. (2005) Ventricular size mapping in a transgenic model of schizophrenia. Dev. Brain Res., 154: 35-44
Torres, G., Meeder, B.A., Hallas, B.H., Gross, K.W. and Horowitz, J.M. (2005) Preliminary evidence for reduced social insteractions in Chakragati mutants modelling certain symptoms of schizophrenia. Brain Res., 1046: 180-186
Dawe, G.S. and Ratty, A.K. (2007) The chakragati mouse: A mouse model for rapid in vivo screening of antipsychotic drug candidates. Biotech J., 2
Torres, G., Hallas, B.H., Gross, K.W., Spernyak, J.A. and Horowitz, J.M. (2008) Magnetic resonance imaging and spectroscopy in a mouse model of schizophrenia. Brain Res. Bull. 75: 556-561
Verma, V., Chay, H.T., Ong, W.Y., Grigoryan, G.A., Jones, C.A., Stolzberg, D., Salvi, R., Gross, K.W., Ratty, A.K. and Dawe, G.S. (2008) The chakragati mouse shows deficits in prepulse inhibition of acoustic startle and latent inhibition. Neurosci. Res., 60: 281-288

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Tags: biotech, chakra, chakragati, ckr, disease, efficacy, model, neurobehavioural, schizophrenia, screening

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