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
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