We propose in this phase I SBIR application to generate and market a genetic model for a human psychiatric disorder(s) in mice by generating a loss of function mutation in the murine gene Wolframin 1 (mWfsl) through homologous recombination in ES cells. Both, homozygous and heterozygous animals of the resulting mouse strain will be phenotypically characterized at the behavioral, pharmacological, neurological and neuro-endocrine level. The characterized mouse strain will be made available to commercial clients for both screening services for lead drug evaluation and as a substrate for further drug target discovery and characterization projects. In phase II we will use the mWfs 1 loss of function strain for the in vivo validation of compounds derived from a cell based high throughput screen for compounds, which are able to increase wolframin expression at the RNA level. Published human linkage data and a large amount of preliminary results generated in mouse from our own laboratories indicate that Wfs 1 loss of function mutations will have profound effects on higher cognitive functions without generating embryonic lethality. The rational for the proposed project is based on published findings and our own preliminary data: 1). Mutations in the Wolframin gene are causal to the Wolfram syndrome, a progressive neurodegenerative disorder associated with juvenile onset diabetes mellitus. 2). Psychiatric illness occurs in most cases of Wolfram syndrome and heterozygous carriers are 26 times more likely to present with a major mental illness during their lifetime. 3). Expression of murine Wfsl is dynamically regulated, in a brain locus specific manner, in several established models of psychiatric disease in mice where: a) mWfsl is down-regulated in the prefrontal cortex of mice reared in isolation as compared to mice reared in enriched environments, b) Wfsl is up-regulated in the olfactory tubercle in a PCP model of psychosis. We hypothesize that loss of function of mWfs 1 will have phenotypic effects at the behavioral and neurological level which will enable novel drug discovery efforts. However, neither the human linkage studies, the human pathophysiology of Wolfram syndrome patients or carriers, nor the animal data gathered so far, allow a prediction about the precise behavioral phenotype of mWfs 1 loss of function mutation in mice. The fact that we do not yet know which specific syndrome will be modeled is not a liability of this proposal. Wolfram syndrome is a bona fide human disease that shows markedly enhanced vulnerability to several forms of mental illness. In Phase I of this application we seek funding only for the behavioral and pharmacological characterization of homozygous and heterozygous Wfs 1 k/o animals.
