The role of TLR signaling in fetal brain injury from prenatal inflammation

项目摘要 感染和炎症仍然是导致流产和婴儿发病率和死亡率的重要因素。 妊娠期母体感染是不良神经行为结局的重要危险因素， 包括认知延迟、精神分裂症、自闭症和智力迟钝。常见的感染微生物 孕妇包括E.大肠杆菌、B群链球菌、支原体和脲原体;所有这些病原体 与围产期损伤有关，暴露于这些生物体与长期 对后代的影响。这些特殊的微生物是最有可能促成围产期发病率 通过子宫腔中的定殖和/或感染，而不是来自母亲的全身感染。 了解这种更常见的临床情况，我们开发了小鼠模型， 子宫内感染和炎症。我们实验室的研究表明， 暴露于宫内感染导致胎儿和出生后脑损伤。最近，我们有 证明即使是低剂量的子宫内炎症模型， 子宫内的反应-子宫腔中的细菌副产物可导致胎儿和产后脑 损伤虽然母亲和胎儿胎盘单位中的免疫应答的激活被认为是 Toll样受体在胎儿脑损伤发病机制中起着至关重要的作用， (TLR)炎症诱导的胎儿脑损伤的母亲、胎盘和/或胎儿中的信号传导途径没有 被阐明。直到先天免疫途径机械地负责不良后果， 产前感染被发现，治疗策略不能开始。靶向母体TLR通路可能是 预防不良结局的重要治疗策略;然而，如果 病原体或病原体副产物可在缺乏母体免疫的情况下直接激活胎儿TLR TLR治疗不能到达胎儿室。此外，如果免疫介质激活非- TLR通路，无论是在母亲或胎儿，靶向TLR信号传导将无法防止结果。它 母体和/或胎儿TLR信号传导是否是暴露于 产前炎症;因此，尚未寻求针对这些途径的指导性疗法。我们假设 1)产前感染引起的胎儿脑损伤是通过一个共同的途径发生的， 细菌病原体和/或被激活的特异性TLR; 2）母体TLR信号传导是足够的，但不是 必要的，炎症诱导的脑损伤，和3）胎儿（和胎盘）TLR信号传导是足够的， 炎症引起的胎儿脑损伤在TLR途径和胚胎中使用遗传操作的小鼠 转移技术，我们将创建母体和胎儿-胎盘单位分离的妊娠母鼠 基因型因此，通过我们的宫内感染小鼠模型和描述的结果，我们将能够 确定母体与胎儿TLR信号传导在暴露于产前感染后不良结果中的作用。

Project Summary Infection and inflammation remain a significant contributor to pregnancy loss and infant morbidity and mortality. Maternal infections during pregnancy represent a significant risk factor for adverse neurobehavioral outcomes, including cognitive delay, schizophrenia, autism and mental retardation. Common organisms that infect pregnant women include E. coli, Group B streptococcus, Mycoplasma and Ureaplamsa; all of these pathogens are implicated in perinatal injury and exposure to these organisms has been associated with long term consequences for the offspring. These particular organisms are most likely to contribute to perinatal morbidity through colonization and/or infection in the uterine cavity not from systemic infection of the mother. Understanding this more common clinical scenario, we have developed mouse models that accurately mimic intrauterine infection and inflammation in the human. Research from our laboratory has demonstrated that exposure to intrauterine infection results in both fetal and postnatal brain injury. More recently, we have demonstrated that even with a low dose model of intrauterine inflammation-in which there is minimal immune response in the uterus-that bacterial by-products in the uterine cavity can cause fetal and postnatal brain injury. While activation of the immune response in both the mother and feto-placental unit is believed to play a crucial role in the pathogenesis of fetal brain injury from prenatal infection, the necessity of Toll-like receptor (TLR) signaling pathways in the mother, placenta and/or fetus to inflammation-induced fetal brain injury has not been elucidated. Until the innate immune pathways mechanistically responsible for adverse outcomes from prenatal infection are revealed, therapeutic strategies cannot begin. Targeting maternal TLR pathways may be an important therapeutic strategy to prevent adverse outcomes; however, this approach may be for naught if pathogen or pathogen by-products can directly activate fetal TLR in the absence of a maternal immune response and TLR therapies do not reach the fetal compartment. Moreover, if immune mediators activate non- TLR pathways, in either the mother or fetus, targeting TLR signaling would fail to prevent outcomes. It remains unknown whether maternal and/or fetal TLR signaling is a crucial step in brain injury from exposure to prenatal inflammation; as such, directive therapies to these pathways have not been pursued. We hypothesize 1) that fetal brain injury from prenatal infection occurs by a common pathway regardless of the initiating bacterial pathogen and/or the specific TLR that is activated; 2) maternal TLR signaling is sufficient, but not necessary, for inflammation-induced brain injury, and 3) that fetal (and placenta) TLR signaling is sufficient for inflammation-induced fetal brain injury. Using genetically manipulated mice in the TLR pathway and embryo transfer technique, we will create pregnant dams in which the mother and feto-placental unit are divergent genoyptes. Thus, with our mouse model of intrauterine infection and delineated outcomes, we will be able to determine the role of maternal vs. fetal TLR signaling in adverse outcomes after exposure to prenatal infection.