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: 8608005
• 负责人: AKIRA SAWA
• 金额: $ 35.32万
• 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/8608005
• 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，通常在青春期后发生。越来越多的证据表明，出生后大脑成熟障碍（包括中间神经元缺陷）发挥着重要作用。然而，对 SZ 的机制理解还不够成熟。尽管精神障碍影响大脑，但阻碍这一进展的一个主要限制是难以获取患者的神经元细胞。为了克服这一困境，由 PI 担任主任的项目系统地收集了 SZ 患者和正常对照的组织和细胞（淋巴细胞、淋巴母细胞、成纤维细胞、诱导多能干细胞和通过鼻活检的嗅觉神经元）。血细胞的收集旨在探索高通量外周生物标志物。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，当细胞暴露于增加的葡萄糖浓度后，SZ 和对照之间的这种差异更加明显。氯氮平使 SZ 中过量的 ROS 部分恢复正常，临床上用于治疗 SZ 患者。其他发现揭示了 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，表明前扣带皮层中谷胱甘肽减少。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。我们假设这种易感性与 SZ 作为性状标记有关，在神经元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背后可能的细胞机制，例如谷胱甘肽 (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问题。我们将讨论精神安定药是否可以减少与这种易感性相关的过量活性氧。然后，在最终目标中，我们将检查我们从中获得细胞的同一组受试者大脑中的生化变化。我们计划研究在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。 SZ 病理学中氧化应激的证据在 SZ 研究历史中已有报道，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，这是该疾病的关键病理生理学。因此，我们对人类细胞，特别是神经元的研究可能为 SZ 研究提供重要信息。