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

描述(由申请人提供)：本研究建议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质损伤(由于持续的微小支原体羊膜内感染(IAI)所致)方面的疗效，并将神经行为结果与新生儿脑损伤的神经病理结果联系起来。我们的中心假设是，用一种特定的大环内酯类抗生素阿奇霉素(AZI)对延长的微小支原体IAI进行产前治疗将减轻脑白质损伤的胎儿起源，并降低围产期神经损害的严重程度。实验方法将利用我们的非人灵长类IAI模型，在怀孕105天时中期接种微小解脲支原体(105CFU/ml，血清型1)。我们预测，我们的新方法将模仿解脲支原体的懒惰本质。通过延长胎儿对这些微生物的暴露时间和由此产生的炎症环境，可能会加重脑室周围白质损伤，从而导致妊娠期间的感染。胎儿心血管血流动力学和局部循环变化将通过多普勒超声监测，并与发育关键期的胎儿大脑磁共振成像(MRI)相关联。对胎儿(子宫内)和婴儿的大脑进行系列核磁共振扫描，将有助于深入了解微小胎儿IAI期间和新生儿期发生的潜在脑白质损伤的性质和时间。出生后随访研究旨在将神经肌肉灵巧性障碍、神经行为和认知异常等不良神经发育结果与慢性围产期白质炎症(如小胶质细胞增多症、星形胶质细胞增多症和少突胶质细胞成熟受阻)的神经病理结果相关联。一些机械性的终点将被确定，这将有助于我们理解解脲支原体感染、胎儿炎症反应和血流动力学适应之间的因果联系，这些因素预示着脑白质损伤和神经功能障碍。羊水中前列腺素E_2、前列腺素F_2�、促炎细胞因子(IL-6、肿瘤坏死因子-�、IL-1�)、白细胞总数和子宫收缩功能与羊水、胎儿脐血和新生儿标本中微小支原体的定量培养和聚合酶链式反应相关，以建立抗生素治疗的预后指标，有助于改善临床治疗决策。我们应用程序的一个主要优势在于，我们能够在独特和相关的动物模型中，通过出生后对神经行为和认知发育的功能评估来结合“宫内”治疗策略，以防止不利的神经后遗症。考虑到我们多学科调查团队的资源和专业知识的汇聚，我们的科学方法很有可能转化为 将减少早产婴儿的不良神经后遗症的临床应用。]

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.]