Intrauterine Inflammation & Adverse Neurological Outcome

描述（由申请人提供）：早产是新生儿发病率和死亡率的主要原因。许多早产患者有局部子宫内炎症的证据，通常没有可识别的感染病因。宫内炎症的存在增加了新生儿不良神经系统结局的风险，包括脑瘫。虽然近年来在将炎症状态与异常神经元发育相关联方面取得了重大进展，但导致暴露于宫内炎症的婴儿神经学结局不良的基本机制仍不清楚。我们的工作假设是，局部子宫内炎症激发母体炎症反应，这反过来又引起胎儿大脑中的无菌炎症反应，导致新生儿大脑发育异常。为了更准确地模拟临床观察到的情况，我们建立了一个局部子宫内炎症的小鼠模型。其他动物模型使用母亲的全身炎症或对新生儿大脑的直接炎症刺激作为研究炎症对神经元发育的影响的手段。这些研究被激活的其他途径所混淆，这些途径不是局部子宫内炎症所固有的。因此，由于它们不能代表大多数炎症诱导的早产病例中临床发生的情况，因此它们无法充分识别导致早产儿不良神经学结局的机制和途径。由于我们的模型是一个局限性宫内炎症，我们能够调查的信号转导通路和初级介质激活的胎儿在响应于局限性宫内炎症和这些通路的激活在异常神经发育的影响。本研究提出了三个具体的目的：1）确定宫内炎症是否在胎儿和新生儿脑中引起局部的、器官特异性的炎症反应，以及该反应是由LPS直接介导的还是继发于不涉及LPS转移的母体宫内炎症; 2）确定响应于宫内炎症的关键母体和胎儿细胞因子的产生是否是胎儿脑中发生炎症反应的机制;和3）确定响应于局部子宫内炎症产生的促炎介质是否损害发育中的胎儿脑。通过靶向炎症诱导的神经元损伤中涉及的主要介质和精确机制，我们将使用我们的模型来探索潜在的治疗方案，以减少暴露于宫内炎症的不良新生儿结局。

DESCRIPTION (provided by applicant): Preterm birth is a leading cause of neonatal morbidity and mortality. Many patients with preterm birth have evidence of localized intrauterine inflammation, often without an identifiable infectious etiology. The presence of intrauterine inflammation increases the risk for adverse neurological outcome in the neonate, including cerebral palsy. While there has been significant progress in recent years with respect to correlating an inflammatory state with abnormal neuronal development, the fundamental mechanisms responsible for poor neurological outcome in infants exposed to intrauterine inflammation remain unclear. Our working hypothesis is that localized intrauterine inflammation incites a maternal inflammatory response, which in turn provokes a sterile inflammatory response in the fetal brain resulting in abnormal development of the neonatal brain. To more accurately mimic what is observed clinically, we have created a mouse model of localized intrauterine inflammation. Other animal models use systemic inflammation in the mother or a direct inflammatory stimulus to the neonatal brain as the means to investigate the effects of inflammation on neuronal development. These studies are confounded by the activation of other pathways that are not inherent to localized intrauterine inflammation. Therefore, since they do not represent what occurs clinically in most cases of inflammation-induced preterm birth, they are unable to adequately discern the mechanisms and pathways responsible for adverse neurological outcome in the preterm infant. Since our model is one of localized intrauterine inflammation, we are able to investigate the signal transduction pathways and primary mediators activated in the fetus in response to localized intrauterine inflammation and the effect of the activation of these pathways in abnormal neurological development. Three specific aims are addressed in this proposal: 1) to determine if intrauterine inflammation provokes a localized, organ specific inflammatory response in fetal and neonatal brain and whether this response is mediated directly by LPS or is secondary to maternal intrauterine inflammation not involving transfer of LPS; 2) To determine if production of key maternal and fetal cytokines in response to intrauterine inflammation are the mechanisms by which an inflammatory response occurs in the fetal brain; and 3) to determine if proinflammatory mediators produced in response to localized intrauterine inflammation damage the developing fetal brain. By targeting the primary mediators and precise mechanisms involved in inflammation-induced neuronal damage, we will use our model to explore potential therapeutic options to reduce adverse neonatal outcome from exposure to intrauterine inflammation.