High throughput marker for cognitive deficit: cellular autofluorescence

认知缺陷的高通量标记：细胞自发荧光

• 批准号: 9904752
• 负责人: AKIRA SAWA
• 金额: $ 54.25万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-13 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904752
• 关键词: Address; Affect; Age; Animal Model; Animals; Biological; Biological Assay; Biological Markers; Blood; Blood Cells; Blood specimen; Brain; Cell Nucleus; Cells; Clinical; Cognitive; Cognitive deficits; Complement; Data; Diagnosis; Diagnostic; Disease; Early Diagnosis; Expression Profiling; Functional disorder; Gender; Gene Expression; Genetic Transcription; Glycolysis; Human; ITGAM gene; Impairment; Link; Macrophage-1 Antigen; Measures; Mediating; Meta-Analysis; Methodology; Microglia; Molecular; Mus; Nuclear; Oxidative Stress; Oxides; Pathologic; Pathology; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Post-Translational Protein Processing; Predisposition; Prefrontal Cortex; Race; Reader; Reporting; Research; Role; Schizophrenia; Sorting - Cell Movement; Stress; Sudan Black B; Synapses; System; Testing; Translational Research; Wisconsin; base; brain dysfunction; flexibility; high throughput screening; human stem cells; human study; innovation; mouse model; neural circuit; novel therapeutic intervention; peripheral blood; pre-clinical; predictive marker; receptor; receptor expression; stem cell biology; trait

ABSTRACT For the past decade, several lines of evidence have shown a direct role for oxidative stress in the pathology of schizophrenia (SZ). Although peripheral changes associated with oxidative stress may be useful to establish biomarkers for the disease, connecting such peripheral changes to brain dysfunction has not yet been fully established. Furthermore, there is a need to develop high throughput assays for measuring such peripheral changes. We recently found that oxidative stress-associated endogenous autofluorescence (AF) is aberrantly augmented in SZ cells. AF is regulated by the GAPDH stress cascade, and the extent of AF is negatively correlated with cognitive flexibility evaluated by the Wisconsin Card Sorting Test. Meanwhile, we have recently found that the selectively activated GAPDH stress cascade in microglia in the prefrontal cortex is likely to mediate cognitive inflexibility in an oxidative stress-associated mouse model. We have observed that expression of Cd11b (a key factor for microglia to target to synapse) is regulated by the GAPDH stress cascade in this mouse model. Based on these promising preliminary data, we hypothesize that activation of the GAPDH stress cascade and associated altered AF triggers pathological changes in microglia, which in turn affects synaptic connectivity in the prefrontal cortex that underlies cognitive flexibility. To address this hypothesis, we propose the following three aims: 1) to establish a high throughput assay that measures cellular AF from human blood samples; 2) to identify specific cognitive domain(s) that is correlated with and predicted by augmented AF in blood cells; and 3) to identify a molecular mechanism by which the GAPDH stress cascade mediates cognitive inflexibility in an oxidative stress-associated animal model. Through these three Aims, we seek the translational potential of intervening in the GAPDH stress cascade to ameliorate cognitive deficits by using AF in blood cells as an objective high throughput marker.

摘要 在过去的十年里，有几条证据表明氧化应激在糖尿病的病理过程中起着直接的作用。 精神分裂症(SZ)。尽管与氧化应激相关的外周变化可能有助于建立 这种疾病的生物标志物，将这种外周变化与大脑功能障碍联系起来，还没有完全得到证实。 已经成立了。此外，需要开发用于测量这种外围设备的高通量分析 改变。我们最近发现，氧化应激相关的内源性自体荧光(AF)异常 在SZ细胞中增强。房颤受GAPDH应激级联调节，房颤程度为负值 与威斯康星卡片分类测验评估的认知灵活性相关。与此同时，我们最近 发现选择性激活的GAPDH应激级联在前额叶皮质的小胶质细胞中可能会 在氧化应激相关的小鼠模型中调节认知不灵活。我们观察到， 小胶质细胞靶向突触的关键因子CD11b的表达受GAPDH应激的调节 在这个小鼠模型中层叠。基于这些有希望的初步数据，我们假设 GAPDH应激级联和相关的房颤改变触发小胶质细胞的病理变化，进而 影响作为认知灵活性基础的前额叶皮质的突触连接性。要解决这个问题 假设，我们提出了以下三个目标：1)建立一种高通量的检测细胞 从人的血液样本中提取房颤；2)确定与房颤相关和预测的特定认知领域(S 通过增加血细胞中的AF；以及3)确定GAPDH应激的分子机制 在氧化应激相关的动物模型中，CASCADE调节认知不灵活。通过这三个 目的，我们寻求干预GAPDH应激级联反应以改善认知的翻译潜力 通过使用血细胞中的房颤作为客观的高通量标记物来检测缺陷。