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

基本信息

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
项目类别：
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

项目摘要

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亲抗生素治疗在预防或减轻新生儿脑白质损伤（由于长期微小 U.parvum 羊膜内感染，IAI）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相关联，我们的中心假设是用特定的大环内酯类抗生素阿奇霉素对长期 U.parvum IAI 进行产前治疗。 (AZI) 将减轻胎儿脑白质损伤并降低围产期神经损伤的严重程度。该实验方法将利用我们的非人类灵长类动物 IAI 模型，并在妊娠中期接种 U.parvum (105 CFU/ml，我们预测，我们的新方法将通过延长胎儿接触这些血清的时间来模仿人类怀孕期间解脲支原体感染的惰性。微生物和由此产生的炎症环境，可能会加剧胎儿心血管血流动力学和局部循环变化，以响应长期的小U.parvum IAI和母亲产前治疗，将通过多普勒超声检查并与磁共振成像相结合进行监测。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发育关键时期的胎儿大脑的性质和时间。 U.parvum IAI 期间和新生儿期发生的白质损伤旨在将不良神经发育结果（例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）的神经病理学结果相关联。、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因果关系。解脲支原体感染、胎儿炎症反应和血流动力学适应预示着胎儿炎症反应的脑白质损伤和神经功能障碍，即羊水中 PGE2、PGF2 的水平。、促炎细胞因子（IL-6、TNF-¿、IL-1¿）、白细胞总数和子宫收缩力将与来自羊水、胎儿脐带血和新生儿样本的微小 U.parvum 的培养和 PCR 定量相关，为了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，我们应用的一个主要优势在于我们能够将“子宫内”治疗策略与产后功能评估相结合，以预防不良神经系统后遗症。鉴于我们多学科研究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独特且相关的动物模型。临床应用将减少早产人类婴儿的不良神经系统后遗症。]