Low birth weight, uterine infection, and nitric oxide

超出提供的空间。泌尿生殖道感染和宿主因素通常与低出生体重有关，特别是在少数人群中大多数病原体，包括大肠杆菌，都会形成独特的毒力机制来定植和入侵泌尿生殖道细菌黏附素，如E.ol的菌毛与宿主组织受体相互作用，允许向上感染和相关并发症。一氧化氮(NO)，一种具有多种功能的气体分子，包括调节感染和免疫，被报道由子宫胎盘组织产生。本项目的目标是评估是否NO通过调节细菌侵入细胞来调节子宫感染的严重程度。我们假设没有系统调节子宫胎盘细菌受体，衰变加速因子(DAF)和细菌入侵我们认为这一新的机制可能在感染的严重性和围产期的发病率(如低出生体重)中发挥作用。这些假说将通过追求三个特定的目标来检验。特定的目标1将确定NO是否抑制DR+E线圈附着和内化到上皮细胞中，以及这是否通过抑制DAF的表达而发生。子目标1.1将表征NO的产生，子宫上皮细胞系、Ishikawa、RL-95和HEC-1细胞中的一氧化氮合酶(NOS)酶亚目的1.2将检验该假说是否操纵这些细胞中的NO合成，将改变DR+E线圈的附着和内化子目标1.3将检验上皮细胞DAF蛋白和mRNA的含量受NO系统调节的假说特定的目标2将确立调控大鼠的NO合成将通过改变实验性宫内感染的子宫和血管系统的DAF含量来改变感染的严重程度子目标2.1将检验以下假设：子宫胎盘组织中DR*E线圈或B组链球菌(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将检验改变的假设在DAF中，子宫胎盘和血管组织中的含量与NO合成中的Chang+ES有关，特异性目标3将检测NO合成的抑制和实验性宫内感染DR E线圈或GBS感染是否导致大鼠胎儿生长受限。如果是这样的话，是否没有供体可以逆转胎儿生长受限子目标3.1将检验抑制NO合成与宫内DR+E线圈或GBS感染对胎儿和胎盘生长具有协同有害影响的假设子目标3.2将检验没有供体可以逆转子宫胎盘和血管组织以及胎儿生长限制执行部位========================================Section End===========================================中DAF表达增加的假设

EXCEED THE SPACE PROVIDED. 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 PERFORMANCE SITE ========================================Section End===========================================