Oxidative stress and schizophrenia: combination of cell biology and brain imaging

描述(申请人提供)：精神分裂症(SZ)是一种衰弱的精神疾病，通常在青春期后发展。越来越多的证据表明，干扰在出生后大脑成熟中发挥了作用，其中包括神经元间缺陷。然而，对SZ的机械性认识还不是很成熟。尽管精神障碍会影响大脑，但阻碍这一进展的一个主要限制是很难接触到患者的神经细胞。为了克服这一困境，PI担任主任的项目系统地收集了SZ患者和正常对照组的组织和细胞(淋巴细胞、淋巴母细胞、成纤维细胞、诱导多能干细胞和鼻活检的嗅神经元)。采集血细胞的目的是探索高通量的外周生物标志物。在我们的初步研究中，我们观察到与对照细胞相比，SZ淋巴母细胞和嗅觉神经元中的活性氧物种(ROS)水平过高。有趣的是，SZ和对照组之间的这种差异在细胞暴露于更高的葡萄糖浓度后更加明显。氯氮平可使SZ内过量的ROS部分恢复正常，临床用于SZ患者的治疗。更多的发现揭示了SZ细胞中的氧化还原失衡。我们对提供组织/细胞样本的个体进行了磁共振波谱分析，并获得了初步数据，表明前扣带回皮质中的谷胱甘肽减少。根据我们的初步数据和前人的研究，我们假设SZ患者的细胞可能具有导致氧化应激的内在易感性，这可能在葡萄糖超负荷下进一步表现出来。我们假设这种敏感性与SZ作为一种特征标记有关，SZ在神经细胞和非神经细胞中都很常见。在这项建议中，我们计划通过测量ROS和蛋白质氧化水平以及研究这种敏感性可能的细胞机制，如谷胱甘肽(GSH)级联、NADPH氧化酶、NAD/NADH和线粒体功能，来更详细地解决这种细胞敏感性问题。我们将讨论抗精神病药是否可以减少与这种敏感性相关的过量ROS。然后，在最终目标中，我们将检查从我们获得细胞的同一组受试者大脑中的生化变化。我们计划检查淋巴母细胞和嗅觉神经元中观察到的细胞变化和易感性在大脑中的表现方式。氧化应激在SZ的病理机制中的证据已经在SZ的研究历史中被报道，现在强调的是氧化应激可以引起SZ相关的中间神经元缺陷，这是这种疾病的关键病理生理机制。因此，我们对人类细胞，特别是神经元的研究，可能会为SZ的研究提供重要信息。

DESCRIPTION (provided by applicant): Schizophrenia (SZ) is a debilitating mental illness typically developing after puberty. Accumulating evidence suggests role for disturbances in postnatal brain maturation, which includes interneuron deficits. However, mechanistic understanding of SZ is not well developed. One major limitation that has blocked the progress, although mental disorders affect the brains, is the difficulty in accessing neuronal cells from patients. To overcome this dilemma, the program for which the PI serves as director, has systematically collected tissues and cells (lymphocytes, lymphoblasts, fibroblasts, induced pluripotent stem cells, and olfactory neurons via nasal biopsy) from patients with SZ as well as normal controls. Collection of blood cells is aimed to explore high throughput peripheral biomarkers. In our preliminary study, we observed excess levels of reactive oxygen species (ROS) in SZ lymphoblasts and olfactory neurons, compared with control cells. Interestingly, this difference between SZ and controls was accentuated following exposure of cells to increased glucose concentrations. Excess ROS in SZ was partially normalized by clozapine, which is utilized clinically in treatment of patients with SZ. Additional findings revealed redox imbalances in SZ cells. We conducted magnetic resonance spectroscopy of the individuals who provided tissue/cell samples and obtained preliminary data that suggest a decrease glutathione in the anterior cingulate cortex. On the basis of our preliminary data and previous studies by others, we hypothesize that cells derived from SZ patients may have intrinsic susceptibility that results in oxidative stress, which may be further represented under glucose overload. We hypothesize that this susceptibility is associated with SZ as a trait marker, being common in both neuronal and non-neuronal cells. In this proposal, we plan to address this cellular susceptibility in greater detail, by measuring the levels of ROS and protein oxidation as well as investigating possible cellular mechanisms underlying this susceptibility, such as the glutathione (GSH) cascade, NADPH oxidase, NAD/NADH, and mitochondrial functions. We will address whether neuroleptics may decrease excess ROS associated with this susceptibility. Then, in the final Aim, we will examine biochemical changes in brains of the same set of subjects from whom we obtain cells. We plan to examine the manner in which cellular changes and susceptibility observed in lymphoblasts and olfactory neurons are manifested in the brain. Evidence of oxidative stress in the pathology of SZ has been reported in the history of SZ research, which is now highlighted by reports that oxidative stress can elicit SZ-associated interneuron deficit, a key pathophysiology of this disorder. Thus, our study with human cells, especially neurons, may provide important information for SZ research.