Early Gestation as a Sensitive Period to Stress in Sex-Dependent Neurodevelopment

描述（由申请人提供）：胎儿前体细胞促进疾病发展的机制尚不清楚，但可能涉及母体环境、胎盘变化、胚胎性别和表观遗传程序之间的复杂相互作用。由于大多数神经发育障碍在表现上表现出性别偏见，阐明性别特异性易感性产生的机制可能为疾病病因学提供关键见解。我们最近确定了一个敏感时期的早期妊娠，其中压力有性别特异性的长期编程影响后代应激通路神经发育。在机制上，我们已经检测到母亲应激对胎盘炎症细胞因子、生长因子和表观遗传机制的性别特异性影响。根据这些研究，我们假设妊娠早期是一个高度敏感的时期，母体应激对胎盘炎症、表观遗传机制和营养转运的影响会改变发育中的胚胎的程序，从而导致长期的性别特异性后果。因此，我们的研究将检验：1)在高度敏感的妊娠早期，早期产前应激（EPS）如何通过性别特异性胎盘和胚胎炎症、营养转运和表观遗传机制的变化改变应激通路神经发育的长期编程；2)通过抗炎药物或特异性NFkB激活抑制剂治疗EPS的性别特异性编程效应，NBD，3)基因组和蛋白质组学技术，包括chip测序和通路聚焦PCR阵列，分析胎盘和胚胎脑组织，以及整个妊娠期羊水的蛋白质组学分析，以确定在EPS后代神经发育障碍的应激失调编程中重要的潜在可翻译的生物标志物和基因。

DESCRIPTION (provided by applicant): The mechanism through which fetal antecedents contribute to disease development is not understood, though likely involves a complex interaction between maternal environment, placental changes, embryo sex and epigenetic programming. As most neurodevelopmental disorders exhibit a sex bias in presentation, elucidation of the mechanisms by which sex-specific susceptibility arises is likely to provide critical insight into disease etiology. We have recently identified a sensitive period of early gestation where stress has sex-specific long- term programming effects on offspring stress pathway neurodevelopment. Mechanistically, we have detected sex-specific effects of maternal stress on placental inflammatory cytokines, growth factors and epigenetic machinery. From these studies, we hypothesize that early pregnancy is a highly sensitive period for the long- term sex-specific consequences of maternal stress through effects on placental inflammation, epigenetic machinery and nutrient transport altering programming of the developing embryo. Therefore, our studies will examine: 1) how early prenatal stress (EPS) alters the long-term programming of stress pathway neurodevelopment through sex-specific placental and embryonic inflammation, nutrient transport and changes in epigenetic machinery during a highly sensitive period of early gestation, 2) the possible rescue of the sex- specific programming effects of EPS by maternal treatment with an anti-inflammatory or a specific inhibitor of NFkB activation, NBD, and 3) genomic and proteomic technology including ChIP-Sequencing and pathway focused PCR Arrays to analyze placental and embryonic brain tissues and proteomic analysis of amniotic fluid across gestation to identify potential translatable biomarkers and genes important in the programming of stress dysregulation predictive of neurodevelopmental disorders in EPS offspring.