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

• 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
• 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

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(申请人提供)：这项研究和职业发展建议的目标是利用羊膜内和绒毛蜕膜接种微小解脲支原体的非人灵长类动物实验模型来表征在特定的上升子宫感染阶段母体和胎儿体内生物标记物表达谱(即IGFBP-1蛋白分解片段、钙粒蛋白A和B以及膜联蛋白II)之间的机制和时间相互作用。我们的假设是，宫颈阴道液(CVF)、羊水、母血和胎儿血液中特定生物标记物的时空特征将替代宫内感染的进展阶段；类似地，在产妇治疗干预(抗生素和抗炎药)过程中生物标记物表达谱的变化将作为预后指标。胎儿对宫内感染的生理适应将在感染的中晚期和母体治疗的反应中进行评估。补充体外研究将确定候选生物标志物的组织来源和产生率，并解决基质金属蛋白酶在IGFBP-1蛋白水解性切割中的作用。 生理监测以及蛋白质组和分子研究将解决以下问题：(1)可访问的采样点(CVF或母血)中特定生物标记物的免疫检测是否与宫内感染/炎症的进展或消退相关？(2)胎儿血液和/或羊水中的特定生物标记物特征是否与微生物定位和胎儿血流动力学反应有关？(3)子宫活动是否与绒毛蜕膜或羊水中解脲支原体的存在以及母体或胎儿采样点生物标记物特征的变化有关？将确定一些特定的机械性终点，以建立解脲支原体感染进展和早产机制之间的因果联系。子宫收缩功能：羊水中PGE2、PGF2a、细胞因子和MMPs水平与CVF、羊水、母血和胎儿血中IGFBP-1蛋白降解片段、钙颗粒蛋白A和B以及膜联蛋白II的表达相关。胎儿对宫内感染的生理适应将由胎儿呼吸参数(胎儿动脉pH、PO2、SO2%)和胎儿心血管血流动力学的多普勒超声确定。将通过测量皮质醇、DHEAS、雌二醇、孕酮和促炎细胞因子来评估内分泌-免疫相互作用和胎儿HPA轴。这项工作的独特之处在于，在宫内感染的非人类灵长类动物模型(实验性绒毛-蜕膜阶段和羊膜内阶段)中，结合使用了诊断和干预策略。我们期望这些研究的结果将促进临床管理，并促进因宫内感染而面临早产风险的妇女的早期诊断。