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Low birth weight, uterine infection, and nitric oxide

低出生体重、子宫感染和一氧化氮

基本信息

批准号：
7151219
负责人：
CHANDRASEKHAR YALLAMPALLI
金额：
$ 31.79万
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：
2002
资助国家：
美国
起止时间：
2002-12-30 至 2008-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7151219
关键词：
Low birth weight uterine infection

项目摘要

Urogenital infections and host factors are often associated with low birth weight, especially in minority populations Most pathogens, including Escherichia coil, develop unique virulence mechanisms to colonize and invade the urogenital tract Bacterial adhesins such as Dr fimbriae of E col interact with host tissue receptors allowing ascending infection and associated complications Nitric oxide (NO), a gaseous molecule with versatile functions including the modulation of infection and immunity, is reported to be produced by uteroplacental tissues The goal of this project is to assess if NO modulates severity of uterine infection through the regulation of bacterial invasion into cells We hypothesize that NO system regulates the uteroplacental bacterial receptor, decay accelerating factor (DAF) and therefore bacterial invasion We propose that this novel mechanism could play a role in severity of infection and perinatal morbidities such as low birth weight These hypotheses will be tested by pursuing three specific aims Specific Aim 1 will determine whether NO inhibits Dr+ E coil attach- ment and internalization into epithelial cells and whether this occurs through suppression of DAF expression Sub-aim 1.1 will characterize NO production, NO synthase (NOS) enzymes in uterine epithelial cell lines, Ishikawa, RL-95 and HEC-1 cells Sub-aim 1.2 will test the hypothesis if manipulation of NO synthesis in these cells, will alter Dr +E coil attachment and internalization Sub-aim 1.3 will test the hypothesis that the epithelial cell DAF protein and mRNA contents are regulated by NO system Specific Aim 2 will establish that modula- tion of NO synthesis in rats will alter severity of infection through the changes in DAF content of the uterus and vasculature in experimental intrauterine infection Sub-aim 2.1 will test the hypothesis that Dr* E coil or group B streptococcus (GBS) infection in uteroplacental tissues is reduced with increases in NO synthesis and is increased with the inhibition of NO synthesis Sub-aim 2.2 will test the hypothesis that changes in DAF content of uteroplacental and vascular tissues are related to chang+es in NO synthesis Specific Aim 3 will examine if inhibition of NO synthesis and experimental intrauterine Dr E coil or GBS infection results in fetal growth restriction in rats, and if so, whether NO donor can reverse the fetal growth restriction Sub-aim 3.1 will test the hypothesis that inhibition of NO synthesis combined with intrauterine Dr+E coil or GBS infection has synergistic detrimental effects on fetal and placental growth Sub aim 3.2 will test the hypothesis that NO donor can reverse the increases in DAF expression in uteroplacental and vascular tissues and in fetal growth restriction

泌尿生殖道感染和宿主因素往往与低出生体重有关，尤其是在少数民族中，大多数病原体，包括大肠杆菌，发展出独特的毒力机制，侵入泌尿生殖道细菌粘附素如大肠杆菌菌毛与宿主组织受体相互作用允许上行感染和相关并发症一氧化氮（NO），一种具有多功能的气体分子，包括感染和免疫调节在内的功能，据报道是由子宫胎盘产生的。该项目的目的是评估NO是否通过调节子宫内膜组织中的蛋白质来调节子宫感染的严重程度。我们假设NO系统调节子宫胎盘细菌受体，衰变加速因子（decay accelerating factor，ERF）和细菌入侵。在感染的严重程度和围产期发病率（如低出生体重）中发挥作用。通过追求三个特定目标进行测试，特定目标1将确定NO是否抑制Dr+ E线圈附着，分泌和内化到上皮细胞中，以及这是否通过抑制p53表达而发生子目标1.1将表征子宫上皮细胞系中的NO产生、NO合酶（NOS）酶，石川、RL-95和HEC-1细胞子目标1.2将检验假设，如果在这些细胞中操纵NO合成，子目标1.3将测试上皮细胞的粘附和内化的假设，细胞内NO蛋白和mRNA的含量受NO系统的调节。大鼠NO合成的减少将通过改变子宫内膜内容物改变感染的严重程度，子目标2.1将检验Dr* E线圈或B组子宫胎盘组织中链球菌（GBS）感染随着NO合成的增加而减少，随着NO合成的抑制而增加，子目标2.2将检验以下假设：子宫胎盘和血管组织的变化与NO合成的变化有关，特异性Aim 3将检查是否 NO合成抑制和实验性宫内Dr E coil或GBS感染导致胎儿生长子目标3.1将测试大鼠中的胎儿生长限制，如果是，NO供体是否可以逆转胎儿生长限制。假设NO合成抑制与宫内Dr+E coil或GBS感染具有协同作用，对胎儿和胎盘生长的有害影响子目标3.2将检验NO供体可以逆转子宫胎盘组织和血管组织中的RxB表达增加以及胎儿生长受限