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：
9065594
负责人：
Peta Louise Grigsby
金额：
$ 50.63万
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 2017-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9065594
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 prevention Inflammation Inflammatory Inflammatory Response Injury Interleukin-1 Interleukin-6 Life Link MRI Scans 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 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 cognitive development critical period cytokine design dexterity disability fetal fetal brain injury 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.]

DESCRIPTION (provided by applicable): The objectives of this research proposal are to assess the therapeutic effect of antinatal mater 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 neuropathological findings of neonatal brain injury.我们的中心假设是，用特定的大环内酯类抗生素，阿奇霉素（AZI）对长时间的U.parvum IAI进行了产前治疗，将减轻脑白质损伤的胎儿起源，并降低围产神经系统损害的严重程度。实验方法将利用我们的非人类IAI私人模型，并在105天的妊娠时捕获U.Parvum（105 cfu/ml，血清1）的中间接种。我们预测我们的新方法将模仿尿素质量属的顽强性。通过延长胎儿暴露于这些微生物和由此产生的炎症环境，在人类怀孕期间的感染，可能会增加周围的白质损伤。胎儿心血管血流动力学和区域回路的变化对长期的U.parvum IAI和母体触角疗法将通过多普勒超声检查来监测，并在关键时期内与胎儿脑的磁共振成像（MRI）有关。胎儿（在子宫内）和婴儿大脑的连续MRI扫描将洞悉IAI期间和新生儿期间潜在的白质损伤的性质和时机。产后随访研究旨在将不良神经发育结果（例如神经肌肉敏感性，神经肌关系和认知异常）与慢性围产期白质损伤的神经病理学发现与神经病理学发现相关联（即，微神经病，小脂肪酸含量，星形，星形，星形脂肪症和牛皮化元素）。将确定许多机械终点，这将有助于我们理解尿素超倍骨感染之间的因果关系，胎儿炎症反应以及血液动力学适应性，这些适应预示着大脑白质损害和神经系统疾病。胎儿炎症反应的生化标志物的特征，即PGE2，PGF2，PGF2，促炎细胞因子（IL-6，TNF-，IL-1）的羊水水平（IL-6，TNF-，IL-1），总白血细胞近相位和子宫收缩性与量化培养物和NEN的膜片相关性，并与NENAT型和PCR相关。为了建立抗生素疗法的预后指标，这可能有助于改善临床管理决策。我们应用的主要优势在于我们能够在独特且相关的动物模型中纳入“子宫内”治疗策略以防止神经行为和认知发育的产后功能评估。鉴于我们的多学科调查团队的资源和专家的汇合，我们的科学方法很有可能翻译对于临床应用，可以减少过早出生的人类婴儿中不良神经系统的后遗症。]