Neuroinflammation and Neurogenesis in Schizophrenia

精神分裂症的神经炎症和神经发生

• 批准号: 10375000
• 负责人: Cynthia Shannon Weickert
• 金额: $ 35.81万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-20 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375000
• 关键词: Adult; Anatomy; Anti-Inflammatory Agents; Astrocytes; Blood; Blood - brain barrier anatomy; Bone Marrow; Brain; Brain Diseases; Brain region; Cell Maintenance; Cell Proliferation; Cells; Characteristics; Complex; Development; Diagnosis; Endothelial Cells; Exposure to; Future; Gene Expression Profile; Genetic Transcription; Grant; Heterogeneity; Human; ICAM1 gene; Immune; Impairment; Inflammation; Inflammatory; Interneurons; Label; Laboratories; Life; Maps; Microglia; Molecular; Molecular Profiling; Morphology; Nature; Neuroglia; Neurologic; Neuronal Differentiation; Neurons; Pathway interactions; Persons; Phenotype; Population; Positioning Attribute; Proteins; Resolution; Role; Route; Schizophrenia; Signaling Molecule; Subependymal; Tight Junctions; Transcript; Work; adult neurogenesis; angiogenesis; base; brain parenchyma; brain research; cell type; cytokine; density; lateral ventricle; macrophage; migration; monocyte; nerve stem cell; neurogenesis; neuroinflammation; neuropathology; relating to nervous system; response; stem; stem cells; transcriptome sequencing; transcriptomics

Project Summary The ability to generate immature neurons from neural stem cells is blunted in the brains of people with schizophrenia compared to controls. In this grant, we will determine, at the resolution of single cells, how the transcriptional profile of neurogenic cells is altered in schizophrenia in order to identify at which stage neurogenesis is blocked. Bulk RNA sequencing has identified that the most significantly changed transcript within the neurogenic niche in people with schizophrenia is the general macrophage marker, CD163. We will determine if macrophages in the neurogenic niche have the characteristics of helpful or harmful immune cells, and if the type of macrophage varies either with diagnosis (schizophrenia compared to controls) or based on the extent of local inflammation (high compared to low cytokines). We aim to gather evidence to support or negate possible monocyte migration routes across the blood-brain barrier (BBB). We will determine if brain macrophages have morphological features and molecular signatures consistent with differentiation into microglial-like cells, and if this varies with diagnosis. Lastly, we will determine if markers of adult neurogenesis are changed by inflammation and how glia cells may be changed by inflammation and/or by the presence of increased macrophages. By exploring the nature and transcriptomic state of different cell populations in the human neurogenic niche, we can better develop strategies to restore neurogenesis in schizophrenia and other neurological conditions, possibly through targeting macrophages.

项目摘要 从神经干细胞生成未成熟神经元的能力在大脑中减弱， 精神分裂症患者与对照组的比较。在这场比赛中，我们将确定，在 单个细胞的分辨率，神经源性细胞的转录谱是如何改变的， 精神分裂症，以确定在哪个阶段神经发生被阻断。散装RNA 测序已经确定，在细胞内最显著改变的转录本是 精神分裂症患者的神经原生态位是一般的巨噬细胞标志物CD 163。 我们将确定神经原性微环境中的巨噬细胞是否具有以下特征： 有益或有害的免疫细胞，如果巨噬细胞的类型随诊断而变化， （精神分裂症与对照组相比）或基于局部炎症的程度（高 与低细胞因子相比）。我们的目标是收集证据，以支持或否定可能的 单核细胞迁移路线穿过血脑屏障（BBB）。我们将确定大脑 巨噬细胞的形态特征和分子特征与 分化成小胶质细胞样细胞，如果这与诊断不同。最后，我们将 确定成人神经发生的标志物是否被炎症改变，以及胶质细胞如何被炎症改变。 细胞可能因炎症和/或巨噬细胞增多而改变。 通过探索人类不同细胞群的性质和转录组状态， 神经原生态位，我们可以更好地制定战略，以恢复神经发生， 精神分裂症和其他神经系统疾病，可能是通过靶向巨噬细胞。