Compartmental analysis of proteomic biomarkers during intra-uterine infections

子宫内感染期间蛋白质组生物标志物的区室分析

基本信息

批准号：
7384626
负责人：
Peta Louise Grigsby
金额：
$ 8.42万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-13 至 2009-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7384626
关键词：
ANXA2 gene Address Amniotic Fluid Animals Anti-Inflammatory Agents Anti-inflammatory Antibiotics Arteries Azithromycin Bacterial Vaginosis Basic Science Biological Markers Blood Blood Circulation Blood flow Brain Injuries Cardiac Cardiac Output Cardiovascular system Cervical Cesarean section Characteristics Clinical Clinical Management Color Complement Condition Control Animal Data Decidua Depressed mood Descending aorta Development Dexamethasone Diagnostic Diagnostic Procedure Dinoprostone Disease Progression Doppler Ultrasonography Ductus Arteriosus Early Diagnosis Effectiveness End Point Endocrine Environment Estradiol Ethnic Origin Experimental Models Fetal Lung Fetal Monitoring Fetal Ultrasonography Future Gelatinase B Genes Genetic Polymorphism Gestational Age HPSE gene Health Heating Human Hydrocortisone Image Immune In Vitro Individual Indomethacin Infection Inferior vena cava structure Inflammation Inflammatory Inflammatory Response Insulin-Like Growth-Factor Binding Protein 1 Intervention Laboratories Link Macaca mulatta Matrix Metalloproteinases Measurement Mediator of activation protein Microbe Modeling Molecular Molecular Profiling Monitor Monkeys Mycoplasma Mycoplasma hominis Myocardial Neonatal Numbers Pathway interactions Patient currently pregnant Patients Performance Physiologic Monitoring Physiological Adaptation Plasma Play Pregnancy Premature Birth Premature Labor Prematurity of fetus Probability Process Production Progesterone Prostaglandins Proteomics Pulmonary valve structure Race Rate Reproductive Tract Infections Research Research Personnel Research Proposals Resolution Risk Role Sampling Series Simulate Site Source Staging Structure of ductus venosus Structure of umbilical artery Therapeutic Therapeutic Intervention Tissues Translating Ultrasonography, Doppler, Pulsed Ureaplasma Ureaplasma Infections Ureaplasma urealyticum biovar 1 Uterine Contraction Validation Virulence Factors Woman Work amnion amniotic cavity aortic valve career clinical application comparative cytokine expectation fetal fetal blood hemodynamics hypothalamic-pituitary-adrenal axis improved in vivo indexing killings microbial microorganism neonate nonhuman primate novel novel diagnostics novel strategies prevent prognostic programs respiratory response size tool uterine contractility vaginal fluid

项目摘要

DESCRIPTION (provided by applicant): The objectives of this research and career development proposal are to utilize a nonhuman primate experimental model of intra-amniotic and choriodecidual inoculation with Ureaplasma parvum to characterize the mechanistic and temporal interactions among biomarker expression profiles (i.e., IGFBP-1 proteolytic fragments, calgranulins A and B and annexin II), in maternal and fetal compartments during defined stages of ascending uterine infection. It is our hypothesis that spatial and temporal characteristics of specific biomarkers in cervical vaginal fluid (CVF), amniotic fluid, maternal and fetal blood, will act as surrogates for the stage of progression of intra-uterine infection; similarly, changes in biomarker expression profiles during maternal therapeutic interventions (antibiotic and anti-inflammatory agents), will serve as prognostic indicators. Fetal physiological adaptations to intra-uterine infection will be assessed at intermediate and advanced stages of infection, and in response to maternal therapy. Complementary in vitro studies will determine the tissue sources and production rates of candidate biomarkers, and address the role of matrix metalloproteinases in the proteolytic cleavage of IGFBP-1. Physiological monitoring together with proteomic and molecular studies will address the following questions: (1) Will the immunodetection of specific biomarkers in accessible sampling sites (CVF or maternal blood), correlate with the progression or resolution of intra-uterine infection/inflammation? (2) Will specific biomarker profiles in fetal blood and/or amniotic fluid be linked to microbial localization and fetal hemodynamic responses? (3) Will uterine activity correlate with the choriodecidual or amniotic presence of U. parvum, and with alterations in biomarker profiles in maternal or fetal sampling sites? A number of specific mechanistic endpoints will be ascertained to establish the causal links among progression of Ureaplasma infection and mechanisms of preterm labor. Uterine contractility; amniotic fluid levels of PGE2, PGF2a, cytokines and MMPs will be correlated with the expression of IGFBP-1 proteolytic fragments, calgranulins A and B and annexin II in CVF, amniotic fluid and maternal and fetal blood. Fetal physiologic adaptations to intra-uterine infection will be determined by fetal respiratory parameters (fetal arterial pH, pO2, sO2%), and by Doppler ultrasonography of fetal cardiovascular hemodynamics. Endocrine-immune interactions and the fetal HPA axis will be evaluated by measurements of cortisol, DHEAS, estradiol, progesterone and pro-inflammatory cytokines. The work proposed is unique in its combined use of diagnostic and interventional strategies in a nonhuman primate model of intra-uterine infection (experimental choriodecidual and intra-amniotic stages). It is our expectation that the results of these studies will advance clinical management and facilitate the early diagnosis of women that are at risk for preterm delivery as a consequence of intra-uterine infection.

描述（由申请人提供）：这项研究和职业发展建议的目标是利用与尿布式parvum的非人类灵长类动物实验模型和脉络膜上的接种，以表征生物标志物表达配置文件之间的机制和时间相互作用（即IGFBP--，IGFBP--，IGFBP--，IGFBP--，IGFBP-- 1蛋白水解片段，钙粘蛋白A和B和膜联蛋白II），在定义的子宫感染阶段的母体和胎儿室中。我们的假设是，特定生物标志物在宫颈阴道液（CVF），羊水，母体和胎儿血液中特定生物标志物的空间和时间特征将充当肠内感染阶段的替代。同样，在母体治疗干预措施（抗生素和抗炎剂）期间，生物标志物表达谱的变化将用作预后指标。将在感染的中间和晚期阶段评估胎儿生理适应对局内感染的适应性，并响应孕产妇治疗。互补的体外研究将确定候选生物标志物的组织来源和生产率，并解决基质金属蛋白酶在IGFBP-1蛋白水解裂解中的作用。生理监测以及蛋白质组学和分子研究将解决以下问题：（1）在可访问的采样部位（CVF或母体血液）中特定生物标志物的免疫试验是否与北极河内感染/炎症的进展或分辨率相关？（2）在胎儿血液和/或羊水中，特定的生物标志物特征是否与微生物定位和胎儿血流动力学反应有关？（3）子宫活性是否与U. parvum的绒毛膜或羊膜化存在以及孕妇或胎儿采样部位的生物标志物谱的改变相关？将确定许多特定的机械终点，以在尿素倍率感染的进展和早产的机制之间建立因果关系。子宫收缩性； PGE2，PGF2A，细胞因子和MMP的羊水水平将与CVF，羊水和母体和胎儿血液中的IGFBP-1蛋白水解片段，钙溶质蛋白A和B和Annexin II相关。胎儿的生理适应对河内感染的适应性将由胎儿呼吸参数（胎儿动脉pH，PO2，SO2％）和胎儿心脏血流动力学的多普勒超声检查确定。内分泌 - 免疫相互作用和胎儿HPA轴将通过测量皮质醇，DHEAS，雌二醇，孕酮和促炎性细胞因子来评估。提出的工作是在非人类的uterine肾上腺内感染模型（实验性脉络化脉络化和散布阶段）中的诊断和介入策略的联合使用。我们期望这些研究的结果将提高临床管理，并促进因局内感染而受到早产风险的妇女的早期诊断。