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

描述（由申请人提供）：双相情感障碍（BPD）影响美国约3%的人口，是发达国家10大残疾原因之一。该疾病的病因尚不清楚，治疗方案要么基于对某些物质的情绪稳定作用的偶然发现的经验观察，要么基于与用于其他精神疾病的精神活性药物的交叉试验。毫不奇怪，这些治疗方案在许多情况下都是需要的，而且它们会带来令人不快的副作用。发现BPD的器质性异常可以促进我们对疾病病因的理解，并帮助我们确定更有针对性的治疗方法。关于BPD的一个特定假设是线粒体功能障碍。我们以前已经表明，线粒体电子传递链（mtETC）的基因的mRNA水平在BPD患者的海马减少，并检查了初级淋巴细胞，以扩展我们的研究结果。淋巴细胞进行低糖应激，结果正常对照组的淋巴细胞上调mtETC水平，以响应低糖应激，而BPD患者的淋巴细胞未能作出反应。这些实验首次表明，细胞对能量应激有一种独特的分子反应，而这种反应在BPD中缺失。我们现在想建立转化的淋巴母细胞系用于进一步的实验操作，因为为了深入研究BPD组织中线粒体功能障碍的假设，我们需要增加每个研究参与者的淋巴细胞的数量和活力。我们已经尝试使用可商购的细胞系进行基因组分析，但是发现基因表达模式中的不可接受的批次效应，这是由于来自对照和患者的淋巴母细胞样细胞系通常在不同的时间和位置收集，并且很少注意细胞系经历的传代次数。因此，我们需要收集我们自己的细胞系，以检查是否可以在严格控制的条件下以保留基因表达模式的方式完成永生化，至少在有限的传代次数内。我们已经与范德比尔特医学院的精神病学系建立了合作关系，通过这一合作，我们可以招募研究参与者，我们选择了R21资助途径来建立一个模型系统，在该系统中，我们可以检查BPD中的线粒体功能。如果结果是肯定的，我们将在未来使用这个系统进行更广泛的分析。 公共卫生相关性：双相情感障碍的原因尚不清楚，治疗方案也没有很好的针对性。我们发现BPD患者的细胞异常涉及线粒体功能。我们正试图复制和扩展这些发现，因为它们为BPD开辟了新的治疗方法，并且它们可以提高我们对导致BPD临床症状的有机机制的理解。

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.