Major depression is emerging as a disease of the central nervous system with a characteristic pathophysiology. For inpatients with major depression, the lifetime mortality due to suicide reaches 15%. Despite a global burden of neuropsychiatric disorders on individual mental health and society's productivity, little is known on mechanisms or molecules that are responsible for these diseases. Accordingly, the identification of the neurobiological underpinnings for mood disorders represents an important challenge in neuropsychiatric research. Complex polygenic mechanisms are likely, with environmental factors contributing to the development of depression and suicidal behavior. However, research efforts have been largely limited to components of brain biology that are affected by antidepressants and mood stabilizers. Microarray technology and genomic characterization represent new investigational developments that allow for unbiased identification of new molecular components and mechanisms of mood disorders. During the award period, the applicant aims to train in the application of microarrays to postmortem human brain studies, to initiate a genomic and molecular characterization of prefrontal cortex dysfunction in depressed patients who died by suicide, and to seek new mechanisms, genes and molecules that contribute to the development of the disease. Preliminary results indicate a rich potential for genomic approaches to psychiatric disorders and hints at a possible molecular classification of depression into unrecognized subtypes.
The specific aims of the study are /) to characterize gene expression profiles in the prefrontal cortex of human subjects, ii) to assess the effect of major depression and suicide on gene expression, iii) to investigate genes and molecular pathways that were affected by the disease, and iv) to develop new understanding of biological mechanisms involved in depression and suicide, with possibilities for designing new genetic mouse models, and uncovering new molecular targets for treatment and prevention of mood disorders. The proposed training plan will enable the applicant to benefit from recent advances in genome sequencing and genomic technologies, and to develop expertise to bridge these approaches to the study of neuropsychiatric disorders. In particular, the applicant will receive valuable training in genomics, statistics and bioinformatics, and in clinical and basic science aspects of brain function. The training program proposes formal courses, supervised training and frequent interactions with several research groups involved in pioneering aspects of genomic research in mood disorders. ? ?
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