Epigenetic mechanisms of behavioural, placental and cognitive impairment in a neurodevelopmental model for schizophrenia

精神分裂症神经发育模型中行为、胎盘和认知障碍的表观遗传机制

• 批准号: 2113285
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2113285
• 关键词: Epigenetic; mechanisms; behavioural; placental; cognitive

A fundamental question in disease research is how stressors experienced during critical developmental periods influence the genesis or 'programming' of adult disease (Estes & McAllister 2016). In particular, stressors experienced during pregnancy have effects on the propensity to develop cognitive disorders in the offspring (Knuessel et al. 2014). Whether this relates to changes directly affecting brain development in utero, or altered maternal behaviour, or a combination of these, is unclear. Further, the mechanisms underlying such effects remain poorly defined. Maternal stressors cause epigenetic modifications (DNA methylation and histone modifications) in offspring brain and placental tissue, which are likely to be key candidate mechanisms leading to altered gene expression, evoking developmental changes in the brain that result in cognitive and behavioural impairment (Akbarian 2014).Further, the placenta plays a crucial role in maternal-fetal interactions and the modulation of fetal adaptive responses that may lead to increased propensity to disease development later in life. Placental development and function is affected by maternal stressors, but how this links to cognitive impairment in offspring is unclear. Recent genome-wide association studies have identified risk factor genes for schizophrenia which adversely affect placentation (Ursini et al. 2017). This may explain the high level of early life complications in patients who later develop schizophrenia. We predict that epigenetic mechanisms mediate the effects of maternal stressors on placental function and hence cognitive development. The proposed project seeks to investigate epigenome x environment interactions that link to schizophrenia development. We will use a multidisciplinary approach to map functional changes along a developmental timeline that links placental morphological development to offspring behavioural traits. Evaluation of placental morphological development, molecular array studies, epigenomic and histological analyses in brain and placenta together with parent-offspring behavioural interactions, cognitive and behavioural analyses in a rodent neurodevelopmental model for schizophrenia will be conducted. The project therefore offers broad scientific training covering mammalian disease and behavioural research, histology, physiology, molecular biology, epigenetic and gene expression analyses.

疾病研究的一个基本问题是关键发育时期经历的压力源如何影响成人疾病的发生或“编程”（Estes & McAllister 2016）。特别是，怀孕期间经历的压力源会影响后代发生认知障碍的倾向（Knuessel et al. 2014）。目前还不清楚这是否与直接影响子宫内大脑发育的变化有关，或者与母亲行为的改变有关，或者与这些因素的组合有关。此外，这种影响的机制仍然不明确。母体应激源会导致后代大脑和胎盘组织发生表观遗传修饰（DNA 甲基化和组蛋白修饰），这可能是导致基因表达改变的关键候选机制，引起大脑发育变化，从而导致认知和行为障碍（Akbarian 2014）。此外，胎盘在母胎相互作用和胎儿发育调节中发挥着至关重要的作用。 适应性反应可能会导致晚年疾病发展的倾向增加。胎盘发育和功能受到母体压力源的影响，但这与后代认知障碍的关系尚不清楚。最近的全基因组关联研究已经确定了精神分裂症的危险因素基因，这些基因会对胎盘形成产生不利影响（Ursini et al. 2017）。这或许可以解释后来患上精神分裂症的患者早期生活并发症发生率较高的原因。我们预测表观遗传机制介导母体应激源对胎盘功能以及认知发展的影响。拟议的项目旨在研究与精神分裂症发展相关的表观基因组与环境的相互作用。我们将使用多学科方法沿着发育时间线绘制功能变化图，将胎盘形态发育与后代行为特征联系起来。将评估胎盘形态发育、分子阵列研究、大脑和胎盘的表观基因组和组织学分析，以及精神分裂症啮齿动物神经发育模型中的亲子行为相互作用、认知和行为分析。因此，该项目提供广泛的科学培训，涵盖哺乳动物疾病和行为研究、组织学、生理学、分子生物学、表观遗传学和基因表达分析。