Identification of disease mechanisms for major psychiatric disorders using genetic mouse models
In recent years, genome wide association studies have identified a large number of genetic risk factors for the major affective disorders and schizophrenia. To determine the impact of these disease-causing factors on the entire organism, and to identify the underlying molecular mechanisms and disease causing pathways, SP7 will use genetic mouse models as an in vivo model system for a systematic analysis on complementary levels. SP7 will focus on promising candidate genes identified for affective disorders and schizophrenia in previous studies.
On the organism level, SP7 will investigate disease-related endophenotypes which cover key aspects of emotional-, social-, and cognitive abilities, as well as neuroendocrine physiology. In addition, we will take into account the multifactorial nature of psychiatric disorders, since research suggests that the environment contributes in manifold ways to the onset and manifestation of psychiatric disease. We will address the consequences of gene-environment interaction by confronting genetic mouse models with specific stressors at defined phases of their lifetime. These phases reflect different windows of disease vulnerability. On the molecular level, we will generate different layers of “omics”-data. Using bioinformatic and systems biology approaches, these data will provide an accurate picture of molecular networks and pathways with a causal relationship to disease.
Moreover, we will apply recently developed technologies, i.e. RNA-guided nucleases (CRISPR/Cas9), to allow the rapid generation of disease models for novel risk factors identified within the Consortium. All of the disease-relevant candidate genes and pathways that are validated in the mouse - as the animal model of choice - are derived from human studies conducted within the Consortium (SP1, SP2, SP3). Moreover, the endophenotypes analyzed in the mouse models are closely correlated to diagnostic criteria applied in patients (SP2, SP4, SP5). Finally, the results of the “omics” approaches are directly compared to bioinformatic predictions (SP1, SP8), as well as to experimental results obtained from human post mortem tissue (SP6), in order to identify and model disease pathways. SP7 will therefore validate genetic risk factors in vivo and unravel the molecular mechanisms which underlie the pathoetiology of the three major psychiatric disorders of interest.
Keywords: affectice disorder, schizophrenia, genetic mouse models, omics