Transgenic Disease Modelling and Translational Studies

In this work package the overall aim is to obtain a thorough understanding of the biological functions of specific molecular structural variants. These variants has in recent years been identified and associated to the mental disorders that are of interest within the iPSYCH project. The variants include rare structural and single nucleotide mutations in the genome conferring high risk of disease. Also factors with lower disease risk, both genetically and environmentally, will be included in the analysis. In this way we are in this work package circumventing the problem of ethiology and pathological heterogeneity and starts by identifying molecular, physiological and anatomical deficits of mental disorders.

The research will be carried out by using cross-species investigation, including subsets of human subjects that are known as carriers of risk factors like rare molecular structural variants. Similar variants will be introduced to mouse and fruit flies samples and thereby help to obtain a more in-depth understanding of the biological functions and effects from the structural variants. The work package will include a combination of state-of-the-art brain imaging, transcriptomic, epigenomic, proteomic, metabolomic and immunological analyses, and system biology. It is expected that the results from this work package will not only provide us with a better understanding of the nature of these molecular variants, but also provide us with new components that can be used as validation for the risk of the disease. This is due to that the variants should provoke a measurable perturbation at molecular, physiological or anatomical level.

4.1. Development of next generation in vivo and in vitro models of mental illness

To obtain a better understanding of the molecular variants associated with mental disorders, new strains of animal models that contain these variants will be created. By using animal models it will be possible to investigate and evaluate the function of each variant and thereby also create a research platform that can be used for developing new and more specific drugs for treatment, but also expand the availability of diagnostic tools.

4.2. Identification of cross-species imaging and biomarker characteristics of disease causes

In recent years the interest in specific physiological expressions and anatomical abnormalities associated with mental disorders, has increased. Data from MR imaging and metabolomic and proteomic technologies will be associated with the molecular structural variants. To obtain the best knowledge of this particular association, the research will focus and be carried out on subset groScientifiups that all are carriers of the variants but does not express the disorder. The consequence from using diseased subjects instead of healthy subjects is that results may be disturbed by other causes from the disorder.

4.3. Identification of molecular disease mechanisms and targets for medical intervention

Pleiotropy (one genetic variant predisposing to different disorders) and genetic heterogeneity (on disorder caused by different risk variants) will be the research target in this part. We will combine the translational investigation from this study with known protein interactions in different organisms extracted from online databases. This should elucidate and provide us with protein networks and signaling pathways that are likely to be associated with the disorders of interest. This will also provide us with an opportunity to identify new drug targets specific for each disorder.