Characterizing stress response variability in immature oligodendrocytes in the context of inflammation

表征炎症背景下未成熟少突胶质细胞的应激反应变异性

• 批准号: 2265139
• 金额: --
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2265139
• 关键词: Characterizing; stress; response; variability; immature

Exposure to prenatal adversities leads to neurodevelopmental (NDDs) and neuropsychiatric (NPDs) disorders. NDDs and NPDs share common pathomechanisms, which prominently include the dysregulation of stress-responsive pathways. Alcohol exposure and systemic inflammation leading to neuroinflammation are among the most prevalent brain prenatal environmental insults. Prenatal alcohol exposure (PAE) leads to fetal alcohol spectrum disorders (FASD; 1% of births in Western countries), which shows overlap with attention deficit hyperactivity disorders (ADHD), anxiety, major depression, vulnerability to addiction, autism spectrum disorders (ASD) and schizophrenia (SZ). Neuroinflammation (e.g. due to intrauterine infection during pregnancy) is a leading cause of prematurity and the commonest cause of NDDs/NPDs (e.g ASD, ADHD, SZ), via diffuse white matter injury (DWMI). In previous lab work, by using epigenomic and transcriptomic analyses in a robust mouse model of neuroinflammation, the activation of complex stress response pathways underlying the blockade of the maturation of oligodendrocyte precursors (OPCs) has been unravelled. The overarching aim of this project is to identify extremely vulnerable OPC subpopulations and decipher the hierarchy and dynamics of combinatory stress-responsive transcription pathways that contribute to block the OPC maturation trajectory, as specific cellular and molecular targets for future therapeutic strategies. For this, single-cell epigenomic (scATAC-Seq) and single-cell transcriptomic (scRNA-seq) approaches will be used to identify the most attractive candidates in the stress-responsive transcription pathways. These candidates will be used in pharmacological pilot studies targeting the identified vulnerable OPC populations to ameliorate their myelination potential in the future.

暴露于产前逆境导致神经发育（ndd）和神经精神（npd）障碍。ndd和npd具有共同的病理机制，其中显著包括应激反应通路的失调。酒精暴露和导致神经炎症的全身性炎症是最常见的大脑产前环境损害。产前酒精暴露（PAE）导致胎儿酒精谱系障碍（FASD；占西方国家新生儿的1%），与注意缺陷多动障碍（ADHD）、焦虑、重度抑郁、易上瘾、自闭症谱系障碍（ASD）和精神分裂症（SZ）重叠。神经炎症（如怀孕期间宫内感染）是早产的主要原因，也是通过弥漫性白质损伤（DWMI）导致ndd / npd（如ASD、ADHD、SZ）的最常见原因。在之前的实验室工作中，通过对神经炎症小鼠模型的表观基因组学和转录组学分析，揭示了抑制少突胶质细胞前体（OPCs）成熟的复杂应激反应途径的激活。该项目的总体目标是确定极度脆弱的OPC亚群，并破译有助于阻断OPC成熟轨迹的组合应激反应转录途径的层次结构和动态，作为未来治疗策略的特定细胞和分子靶点。为此，单细胞表观基因组学（scATAC-Seq）和单细胞转录组学（scRNA-seq）方法将被用于识别应激反应转录途径中最有吸引力的候选基因。这些候选药物将用于针对确定的易受伤害的OPC人群的药理学试点研究，以改善其未来的髓鞘形成潜力。