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Diversity & racial disparity in fetal membrane cytokine signature during infectio

多样性

基本信息

批准号：
8239899
负责人：
RAMKUMAR MENON
金额：
$ 8.18万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-08 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8239899
关键词：
Accounting African American Amniotic Fluid Anti-Bacterial Agents Anti-Inflammatory Agents Anti-inflammatory Asians Autologous Bacteria Bacterial Infections Biochemical Pathway Biological Markers Birth Caucasians Caucasoid Race Complex Complication Conceptions Conditioned Culture Media Culture Media Disease Equilibrium Escherichia coli Etiology Event Fetal Membranes Fetus Functional disorder Genetic Heterogeneity Human IL8 gene Immune response In Vitro Induced Labor Infection Infectious Pregnancy Complications Inflammation Inflammatory Inflammatory Response Intervention Kinetics Laboratories Mediating Mediator of activation protein Membrane Molecular Mycoplasma hominis Neonatal Mortality Organ Pacific Island Americans Pathway interactions Patients Pattern Pilot Projects Porphyromonas gingivalis Pregnancy Premature Birth Premature Labor Production Property Race Repeat Cesarean Section Reporting Resistance Series Source Streptococcus Group B Syndrome System Testing Tissues Tocolytic Agents Ureaplasma urealyticum biovar 1 Uterine Contraction Weight Woman antimicrobial chemokine cytokine fetal intraamniotic infection microbial neonatal morbidity pathogen preterm premature rupture of membranes public health relevance racial difference response

项目摘要

DESCRIPTION (provided by applicant): Spontaneous preterm birth (PTB - <birth before 37 weeks gestation) is a major complication of pregnancy and infection is associated with ~ 50% of the cases. Although PTB has a multifactorial etiology, intraamniotic infection (IAI) and the resulting host (maternal and fetal) inflammatory response is a major component of the disease. Microbial factors are thought to evoke a series of events that compromise the immunological privileges that the fetus enjoys from conception until parturition by stimulating the production proinflammatory cytokines and chemokines that induce labor; however, the immune response is not generalizable. This suggests that initiation of labor may depend on the type of immune response to the type of pathogen. Other tissue and bacterial factor-specific cytokine response have also been reported. Not all cytokines, however, seem to activate the downstream mediators that cause labor and preterm birth suggesting that the biomolecular pathways from infection to preterm birth are complex and that patient-specific interventions targeted to a particular molecular mechanism of preterm birth may be necessary. Understanding the infectious etiology and pathophysiology of PTB is further complicated by disproportionately higher rate of infection and PTB rates in African-Americans than Caucasians. Racial differences in biomarker concentrations are expected to contribute to racial disparity. Furthermore, amniotic fluid consists of multiple antimicrobial factors and the concentration and regulatory mechanisms of these factors are also expected to differ in response to specific IAI and also in different races. Therefore, we hypothesize that host immune response and biochemical pathways of labor are not generalizable but differ between specific bacteria associated with IAI and race. In addition, we hypothesize that the immunomodulatory effects of amniotic fluid is also dependent on bacterial species and maternal race. We will test our hypotheses through the following specific aims; Specific Aim 1: To test the differences in the TH1/TH2 and proinflammatory cytokine/chemokine (IL-8) response and kinetics by normal human fetal membranes exposed to common intraamniotic pathogens including: Ureaplasma parvum, Mycoplasma hominis, E. coli, Group B Streptococcus, P. gingivalis and G. vaginalis. Specific Aim 2: To determine if there are racial differences in TH1/TH2 cytokine signature produced by fetal membranes in response to bacterial species listed above in Aim 1. Specific Aim 3: To test the anti-inflammatory properties of amniotic fluid in maintaining a balanced cytokine response. PUBLIC HEALTH RELEVANCE: Microbial invasion of the intraamniotic cavity and intraamniotic infections and inflammation mediated by a switch in the TH1/TH2 cytokine pattern favoring a proinflammatory response are commonly associated with spontaneous preterm birth. Disproportionately higher rate of infection and preterm births in African Americans and increasing rate of infection associated preterm birth suggest that the infection associated pathophysiologic pathways and biomarkers may not be generalizable and each bacterium may produce their own inflammatory signature and racial disparity will be associated with biomarker profile. In this RO3 application, a pilot study is planned using an in vitro organ explant system for fetal membranes we plan to test differential inflammatory response and racial disparity associated with common intraamniotic pathogens.

描述(申请人提供)：自然早产(妊娠37周前出生)是妊娠的主要并发症，约50%的病例与感染有关。虽然肺结核的病因是多因素的，但羊膜内感染(IAI)和由此引起的宿主(母婴)炎症反应是该病的主要组成部分。微生物因素被认为会引发一系列事件，通过刺激促炎症细胞因子和趋化因子的产生来破坏胎儿从受孕到分娩所享有的免疫特权；然而，免疫反应并不是一概而论的。这表明分娩的开始可能取决于对病原体类型的免疫反应的类型。其他组织和细菌因子特异性的细胞因子反应也有报道。然而，并不是所有的细胞因子都能激活导致分娩和早产的下游介质，这表明从感染到早产的生物分子途径是复杂的，针对早产的特定分子机制的患者特异性干预可能是必要的。非裔美国人的感染率和肺结核发病率比高加索人高得不成比例，这使得理解肺结核的感染病原学和病理生理学变得更加复杂。生物标记物浓度的种族差异预计会导致种族差异。此外，羊水含有多种抗菌因子，这些因子的浓度和调节机制预计也会因特定的IAI和不同的种族而有所不同。因此，我们假设宿主免疫反应和分娩的生化途径不是一概而论的，而是在与IAI和RACE相关的特定细菌之间存在差异。此外，我们假设羊水的免疫调节作用也依赖于细菌种类和母体种族。我们将通过以下特定目标来验证我们的假设：特定目标1：测试正常人胎膜在暴露于常见羊膜内病原体的TH1/TH2和促炎细胞因子/趋化因子(IL-8)反应和动力学方面的差异，这些病原体包括：微小解脲支原体、人型支原体、大肠杆菌、B组链球菌、牙龈假单胞菌和阴道球虫。特异目的2：确定胎膜产生的TH1/TH2细胞因子信号是否存在种族差异，以响应上述目的1中所列的细菌种类。特异目的3：测试羊水在维持平衡细胞因子反应中的抗炎特性。公共卫生相关性：微生物侵入羊膜腔和羊膜内感染，以及由TH1/TH2细胞因子模式的转换所介导的炎症，有利于促炎反应，通常与自发早产有关。非裔美国人感染和早产的比例较高，感染相关早产的发生率增加，这表明感染相关的病理生理途径和生物标记物可能不是一概而论的，每种细菌可能产生自己的炎症特征，种族差异将与生物标记物的分布有关。在R03的应用中，我们计划使用体外胎儿膜器官移植系统进行一项初步研究，以测试与常见羊膜内病原体相关的不同炎症反应和种族差异。