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

氧化应激和精神分裂症：细胞生物学和脑成像的结合

• 批准号: 8426170
• 负责人: AKIRA SAWA
• 金额: $ 33.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-08 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8426170
• 关键词: Address; Affect; Anterior; Antioxidants; Antipsychotic Agents; Area; Biochemical; Biochemical Markers; Biological Markers; Biopsy; Blood Cells; Brain; Brain imaging; Cells; Cellular biology; Clozapine; Collection; Data; Defect; Diabetes Mellitus; Disease; Fibroblasts; Functional disorder; Glucose; Glutathione; Human; Individual; Interneurons; Lymphocyte; Magnetic Resonance Spectroscopy; Measures; Medical; Mental disorders; Metabolic; Metabolic syndrome; Mitochondria; NADH; NADPH Oxidase; Neuroglia; Neurons; Nose; Oxidation-Reduction; Oxidative Stress; Pathology; Patients; Peripheral; Play; Predisposition; Prefrontal Cortex; Proteins; Puberty; Reactive Oxygen Species; Recording of previous events; Reporting; Research; Role; Safety; Sampling; Schizophrenia; Signal Transduction; Testing; Tissues; base; cingulate cortex; induced pluripotent stem cell; lymphoblast; novel therapeutics; oncology; oxidation; postnatal; programs; public health relevance; trait

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.

描述（由申请人提供）：精神分裂症（SZ）是一种使人衰弱的精神疾病，通常发生在青春期后。越来越多的证据表明，在出生后的大脑成熟，其中包括中间神经元缺陷干扰的作用。然而，对SZ的机理认识尚不充分。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难以从患者身上获取神经细胞。为了克服这一困境，PI担任主任的项目系统地收集了SZ患者和正常人的组织和细胞（淋巴细胞、淋巴细胞、成纤维细胞、诱导多能干细胞和嗅觉神经元，通过鼻腔活检）。收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（ROS）水平过高。有趣的是，在细胞暴露于葡萄糖浓度增加后，SZ和对照组之间的这种差异得到了加强。氯氮平可使SZ中过量的ROS部分正常化，临床上用于治疗SZ患者。其他研究结果显示SZ细胞氧化还原失衡。我们对提供组织/细胞样本的个体进行了磁共振波谱分析，并获得了表明前扣带皮层谷胱甘肽减少的初步数据。根据我们的初步数据和其他人之前的研究，我们假设来自SZ患者的细胞可能具有内在易感性，导致氧化应激，这可能在葡萄糖过载下进一步表现出来。我们假设这种易感性与SZ作为一种性状标记有关，在神经元细胞和非神经元细胞中都很常见。在本提案中，我们计划通过测量ROS和蛋白质氧化水平以及研究这种易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，更详细地解决这种细胞易感性。我们将探讨抗精神病药是否可以减少与这种易感性相关的过量ROS。然后，在最后的Aim中，我们将检查从我们获得细胞的同一组受试者的大脑中的生化变化。我们计划研究在淋巴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表现出来的方式。在SZ研究的历史中，氧化应激在SZ病理中的证据已被报道，现在有报道强调氧化应激可引起SZ相关的中间神经元缺陷，这是该疾病的一个关键病理生理。因此，我们对人类细胞，特别是神经元的研究，可能为SZ的研究提供重要的信息。