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：
8372870
负责人：
Peta Louise Grigsby
金额：
$ 62.17万
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/8372870
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-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 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 prognostic indicator 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.] PUBLIC HEALTH RELEVANCE: Intra-amniotic infection by genital Mycoplasmas (i.e., Ureaplasma spp.) is a predominant cause of early preterm birth; arguably the most important unresolved public health issue in obstetric medicine. Preterm infants often have life-long health complications including neurodevelopmental disabilities such as cerebral palsy. This proposal will expand our understanding of the causal relationships among intra-amniotic Ureaplasma infections, fetal brain injury and adverse neurological development in the preterm neonate.

描述：这项研究建议的目标是在预防或在新生儿中进行脑白质损害的治疗方法，并将神经行为与新生儿脑损伤的神经病理学与神经病理学相关联。大型抗生素，阿奇霉素（AZI）将减轻胎儿的起源，围绕围产期神经病学障碍的严重程度。尿素质量属于人类延长的胎儿中的无菌，并导致脑静脉内造成的腹膜和母体产前治疗，并伴有磁性疾病。成像（MRI）l发育时期。慢性围产期白质炎症（即，小胶质细胞增多，星形胶质细胞增多症和少突胶质细胞成熟）。 » ，pro-il-6，tnf-¿建立抗生素的编程器，可以帮助改善临床管理决策。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。] 公共卫生的相关性：生殖器菌落中的肿瘤内感染在产科医学中遭受了不良的公共卫生问题。