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

妊娠中期解脲支原体宫内感染的灵长类动物模型：神经系统疾病的预防

• 批准号: 8666013
• 负责人: Peta Louise Grigsby
• 金额: $ 59.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-20 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666013
• 关键词: Amniotic Fluid; Animal Model; Antibiotic Therapy; Antibiotics; Attentional deficit; Attenuated; Azithromycin; Biochemical Markers; Biological; Blood Circulation; Brain; Brain Injuries; Cardiovascular Physiology; Cardiovascular system; Cerebral Palsy; Cerebrospinal Fluid; Cerebrum; Characteristics; Chronic; Clinical; Clinical Management; Cognitive; Data; Development; Dinoprost; Dinoprostone; Discipline of obstetrics; Doppler Ultrasonography; Encephalitis; Evaluation; Exposure to; Fetal Therapies; Fetus; Genital system; Health; Human; Hypoxia; Impairment; Incidence; Indolent; Infant; Infection; Infection of amniotic sac and membranes; Infection prevention; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Interleukin-6; Life; Link; Macaca mulatta; Macrolide Antibiotics; Magnetic Resonance Imaging; Medicine; Modality; Modeling; Monitor; Mycoplasma; Nature; Neonatal; Neonatal Brain Injury; Neonatal Mortality; Neurodevelopmental Disability; Neurodevelopmental Impairment; Neurologic; Neuronal Injury; Oligodendroglia; Outcome; Perinatal; Perinatal Exposure; Periventricular Leukomalacia; Periventricular white matter injury; Pregnancy; Premature Birth; Premature Infant; Premature Labor; Prevention; Primates; Probability; Prognostic Marker; Prolonged Pregnancy; Public Health; Reporting; Research Design; Research Proposals; Resources; Respiratory System; Respiratory tract structure; Risk; Sampling; Severities; Signal Transduction; Simulate; Staging; TNF gene; Therapeutic Effect; Therapeutic Intervention; Time; Translating; Umbilical Cord Blood; Ureaplasma; Ureaplasma Infections; White Blood Cell Count procedure; amniotic cavity; astrogliosis; central nervous system injury; clinical application; critical period; cytokine; design; disability; fetal; follow-up; hemodynamics; improved; in utero; indexing; insight; intraamniotic infection; microorganism; multidisciplinary; neonatal morbidity; neonate; neurobehavioral; neurodevelopment; neuromuscular; nonhuman primate; novel; novel strategies; pathogen; postnatal; prenatal; prevent; response; treatment strategy; uterine contractility; white matter; white matter damage; white matter injury

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.]

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质损伤（由于长时间的羊膜内感染，IAI）方面的治疗效果，并将神经行为结果与新生儿脑损伤的神经病理学结果联系起来。我们的中心假设是，在产前使用一种特殊的大环内酯类抗生素阿奇霉素（AZI）治疗长时间的uvum IAI，可以减轻胎儿起源的脑白质损伤，降低围产期神经损伤的严重程度。实验方法将利用我们的非人类IAI灵长类动物模型，在妊娠105天接种uv （105 CFU/ml，血清型1）。我们预测我们的新方法将通过延长胎儿暴露于这些微生物和由此产生的炎症环境的时间来模拟人类妊娠期间脲原体感染的惰性性质，并有可能加剧心室周围白质损伤。在胎儿发育的关键时期，将通过多普勒超声监测胎儿心血管血流动力学和局部循环变化对长时间uvum IAI的反应，并结合胎儿大脑磁共振成像（MRI）进行产前治疗。对胎儿（子宫内）和婴儿大脑进行连续MRI扫描，将有助于深入了解在uvum IAI和新生儿期发生的潜在白质损伤的性质和时间。产后随访研究旨在将不良的神经发育结果（如神经肌肉灵活性功能障碍、神经行为和认知异常）与慢性围产期白质炎症（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阻滞）的神经病理学结果联系起来。许多机制终点将被确定，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，这预示着脑白质损伤和神经功能障碍。将羊水、胎儿脐带血和新生儿样本中细小u.m uvum的定量培养和PCR与羊水中PGE2、PGF2水平、促炎细胞因子（IL-6、TNF-、IL-1）、白细胞总数和子宫收缩力等胎儿炎症反应的生化指标进行关联，建立抗生素治疗的预后指标，有助于改善临床管理决策。我们的应用的一个主要优势在于我们能够在一个独特的和相关的动物模型中结合“子宫内”治疗策略来预防不良的神经系统后遗症和产后神经行为和认知发展的功能评估。鉴于我们多学科调查团队的资源和专业知识的融合，我们的科学方法有很高的翻译可能性