Maternal Inflammation Alters Fetal Brain Development via Tumor necrosis Factor-al

描述（由申请人提供）：母亲在怀孕期间的疾病与儿童的各种神经发育问题有关，包括自闭症、精神分裂症、脑瘫和发育迟缓。动物模型表明，母体炎症，即使在胎儿没有感染的情况下，也足以导致大脑发育异常。我们正在使用一种妊娠早期母体炎症模型，其中单次注射脂多糖（LPS）到妊娠小鼠中会导致胎儿大脑中神经发生的突然中断。成年期的挑战时间和行为影响范围与人类的自闭症或精神分裂症最为相似。我们的总体目标是了解炎症细胞因子肿瘤坏死因子-a（TNF-a）如何影响胎儿大脑发育。母体细胞因子和趋化因子可传递到胎儿体内并直接改变神经发生，或可诱导胎儿产生继发性细胞因子并导致神经发育缺陷。此外，我们还观察到胎盘功能的破坏，这可能导致胎儿血液和氧气供应的限制，从而影响神经发育。我们的初步数据表明，TNF-α是母体炎症在胎儿脑和胎盘中的作用的主要介质。我们将使用TNF-α基因缺陷的小鼠来确定TNF-α是否是LPS对胎儿脑发育和胎盘功能的影响所必需的。我们还将用TNF-α的推注处理野生型小鼠以确定其是否足以影响胎儿脑发育和胎盘功能。我们将使用三个主要结果：1）使用胸苷类似物标记分裂细胞的胎儿脑中神经发生和存活率; 2）使用Morris水迷宫中的各种任务的后代认知功能; 3）通过组织学和血流测量分析胎盘结构和功能。这些研究将为母体疾病干扰胎儿神经发育的过程提供机制性见解，并涉及一个单一的基因，该基因可以在临床上靶向保护急性母体疾病期间的胎儿大脑发育。公共卫生相关性：母亲的疾病与儿童大脑发育的许多问题有关，包括自闭症和精神分裂症。我们已经开发了一种小鼠模型，其中怀孕母亲的疾病对胎儿大脑中神经元的数量和出生时间有显着影响。我们正在研究在这个模型中改变胎儿大脑发育的机制，重点是单个分子（TNF-α）的作用，它可以在临床上靶向预防发育性疾病。

DESCRIPTION (provided by applicant): Maternal illness during pregnancy has been associated with a variety of neurodevelopmental problems in the child, including autism, schizophrenia, cerebral palsy and developmental delay. Animal models show that maternal inflammation, even in the absence of infection of the fetus, is sufficient to cause abnormalities in brain development. We are using a model of maternal inflammation during early gestation in which a single injection of lipopolysaccharide (LPS) into pregnant mice causes an abrupt disruption of neurogenesis in the fetal brain. The timing of challenge and spectrum of behavioral effects in adulthood are most similar to autism or schizophrenia in humans. Our overall goal in this proposal is to understand how the inflammatory cytokine tumor necrosis factor-a (TNF-a) affects fetal brain development. Maternal cytokines and chemokines may be transmitted into the fetus and directly alter neurogenesis, or could induce secondary cytokine production in the fetus and result in defects in neurodevelopment. Additionally, we have observed disruptions in placental function which could lead to restriction of blood and oxygen supply to the fetus, and thereby impact neurodevelopment. Our preliminary data indicates that TNF-a is a major mediator of effects of maternal inflammation in both the fetal brain and placenta. We will use mice genetically deficient in TNF-a to determine if TNF-a is necessary for effects on LPS on fetal brain development and placental function. We will also treat wild type mice with a bolus of TNF-a to determine if it is sufficient for effects on fetal brain development and placental function. We will use three primary outcomes: 1) rates of neurogenesis and survival in the fetal brain using thymidine analogs to label dividing cells; 2) cognitive function in the offspring using various tasks in the Morris water maze; 3) analysis of placental structure and function by histology and measurements of blood flow. These studies will provide mechanistic insight into the process by which maternal illness disturbs neurodevelopment in the fetus and implicates a single gene which could be clinically targeted to protect fetal brain development during acute maternal illness. PUBLIC HEALTH RELEVANCE: Maternal illness has been associated with a number of problems in brain development in the child, including autism and schizophrenia. We have developed a mouse model in which illness in the pregnant mother has significant effects on the number and timing of neurons being born in the fetal brain. We are examining the mechanisms by which fetal brain development is altered in this model, focusing on the role of a single molecule (TNF-a), which could be clinically targeted to prevent developmental diseases.