A model system for abnormalities in electron transport genes in bipolar disorder

DESCRIPTION (provided by applicant): Bipolar disorder (BPD) affects approximately 3% of the population in the US, and is among the 10 leading causes of disability in the developed world. The etiology of the disease is unknown and treatment options are either based on empirical observations from serendipitous discoveries of mood stabilizing effects of certain substances, or on cross-over trials with psychoactive medications used in other psychiatric disorders. Not surprisingly, these treatment options are wanting in many cases, and they come with unpleasant side effects. Finding organic abnormalities in BPD can promote our understanding of the etiology of the disease, and help us define better-targeted therapeutic approaches. One particular hypothesis about BPD is mitochondrial dysfunction. We have previously shown that mRNA levels of genes of the mitochondrial electron transport chain (mtETC) are reduced in the hippocampus of BPD patients, and examined primary lymphocytes to extend our findings. The lymphocytes were subjected to low-glucose stress, with the result that lymphocytes from normal controls up-regulated mtETC levels in response to low-glucose stress, while lymphocytes from BPD patients failed to respond. These experiments showed for the first time that cells have a distinct molecular reaction to energy stress, and that this response is missing in BPD. We would now like to establish transformed lymphoblastoid cell lines for further experimental manipulations, since for an in-depth examination of the hypothesis of mitochondrial dysfunction in BPD tissue we will need to increase the number and viability of lymphocytes per study participant. We have tried to use cell lines commercially available for genomic analysis, but found unacceptable batch effects in gene expression patterns due to the fact that lymphoblastoid cell lines from controls and patients are often collected at different times and locations, and little attention is paid to the number of passages the lines are subjected to. Therefore, we need to collect our own cell lines to examine if immortalization under tightly controlled conditions can be accomplished in a manner that retains gene expression patterns, at least over a limited number of passages. We have established a collaboration with the Department of Psychiatry at Vanderbilt Medical School through which we can recruit study participants, and we have chosen the R21 funding route to establish a model system in which we can examine mitochondrial function in BPD. If the outcome is positive, we will employ this system in the future for a more extensive analysis. PUBLIC HEALTH RELEVANCE: The causes of bipolar disorder are unknown, and treatment options are not well targeted. We have found cellular abnormalities in BPD patients that involve mitochondrial function. We are trying to replicated and extend these findings, since they open new treatment approaches for BPD, and since they can improve our understanding of the organic mechanisms leading to the clinical symptoms observed in BPD.