Primate model of mid-gestation Ureaplasma in utero infection: Prevention of neuro

描述（由申请人提供）：本研究计划的目的是评估产前母体抗生素治疗在预防或缓解新生儿脑白色物质损伤（由于长时间的小隐孢子虫羊膜内感染，IAI）方面的治疗效果，并将神经行为结局与新生儿脑损伤的神经病理学结果相关联。我们的中心假设是，产前治疗的延长U.parvum IAI与特定的大环内酯类抗生素，阿奇霉素（AZI）将减轻胎儿起源的大脑白色物质损伤，并降低围产期神经功能缺损的严重程度。实验方法将利用我们的IAI非人灵长类动物模型，在妊娠105天妊娠中期接种微小脲原体（105 CFU/ml，血清型1）。我们预测我们的新方法将模仿脲原体属的惰性性质。通过延长胎儿暴露于这些微生物和由此产生的炎症环境，可能会导致人类妊娠期间的感染，并可能加剧脑室周围白色物质损伤。胎儿心血管血流动力学和局部循环变化响应于延长U.parvum IAI，和母亲产前治疗，将通过多普勒超声监测，并与磁共振成像（MRI）的胎儿大脑在关键时期的发展。胎儿（子宫内）和婴儿大脑的连续MRI扫描将提供对在小隐孢子虫IAI期间和新生儿期发生的潜在白色物质损伤的性质和时间的洞察。产后随访研究旨在将不利的神经发育结果如功能障碍的神经肌肉灵活性、神经行为和认知异常与慢性围产期白色炎症的神经病理学发现（即，小胶质细胞增生、星形胶质细胞增生和少突胶质细胞成熟停滞）。将确定许多机制终点，这将有助于我们理解脲原体感染、胎儿炎症反应和血流动力学适应之间的因果关系，这些因素预示着脑白色物质损伤和神经功能障碍。胎儿炎症反应的生化标志物，即，羊水中PGE 2、PGF 2 β、促炎细胞因子（IL-6、TNF-β、IL-1 β）、总白细胞计数和子宫收缩力的水平将与羊水、胎儿脐带血和新生儿样本中微小脲原体的定量培养和PCR相关，以建立抗生素治疗的预后指标，这可能有助于改善临床管理决策。我们的应用程序的主要优势在于我们能够将“在子宫内”的治疗策略，以防止不良的神经系统后遗症与出生后的神经行为和认知发育的功能评估在一个独特的和相关的动物模型。鉴于我们多学科调查团队的资源和专业知识的融合，我们的科学方法很有可能转化为 涉及临床应用，其将减少早产人类婴儿的不良神经学后遗症。

DESCRIPTION (provided by applicant): The objectives of this research proposal are to assess the therapeutic effect of antenatal maternal antibiotic therapy in preventing or mollifying cerebral white matter damage in the neonate (as a consequence of prolonged U.parvum intra-amniotic infection, IAI) and to correlate neurobehavioral outcomes with neuropathologic findings of neonatal brain injury. Our central hypothesis is that prenatal treatment of prolonged U.parvum IAI with a specific macrolide antibiotic, azithromycin (AZI) will mitigate fetal origins of cerebra white matter injury and decrease the severity of perinatal neurological impairment. The experimental approach will utilize our non-human primate model of IAI, with mid-gestation inoculation of U.parvum (105 CFU/ml, serovar 1) at 105 days gestation. We predict our new approach will mimic the indolent nature of Ureaplasma spp. infections during human pregnancies by prolonging fetal exposure to these microorganisms and the resultant inflammatory milieu, with the potential for intensified periventricular white matter injury. Fetal cardiovascular hemodynamic and regional circulatory changes in response to prolonged U.parvum IAI, and maternal antenatal therapy, will be monitored by Doppler ultrasonography and linked with magnetic resonance imaging (MRI) of the fetal brain during critical periods of development. Serial MRI scans of fetal (in utero) and infant brains will provide insight into the nature and timing of potential white matter injury occurring during U.parvum IAI and in the neonatal period. Postnatal follow-up studies are designed to correlate adverse neurodevelopmental outcomes such as dysfunctional neuromuscular dexterity, neurobehavioral and cognitive abnormalities with neuropathologic findings of chronic perinatal white matter inflammation (i.e., microgliosis, astrogliosis & arrested oligodendrocyte maturation). A number of mechanistic endpoints will be ascertained that will aid in our understanding of the causal links among Ureaplasma infections, fetal inflammatory responses, and hemodynamic adaptations which portend cerebral white matter damage and neurological disabilities. Biochemical markers characteristic of the fetal inflammatory response, i.e., amniotic fluid levels of PGE2, PGF2�, pro-inflammatory cytokines (IL-6, TNF-�, IL-1�), total leukocyte counts and uterine contractility will be correlated with quantitative culture & PCR for U.parvum from the amniotic fluid, fetal cord blood and neonatal samples, in order to establish prognostic indicators of antibiotic therapy which may help improve clinical management decisions. A major strength of our application lies in our ability to incorporate an "in utero" treatment strategy to prevent adverse neurologic sequelae with postnatal functional assessments of neurobehavioral and cognitive development in a unique and relevant animal model. Given the confluence of resources and expertise of our multidisciplinary investigative team, our scientific approach has a high probability of translating to clinical applications which will reduce adverse neurologic sequelae in prematurely born human infants.]