Urogenital infections and host factors are often associated with low birth weight, especially in minority populations. Most pathogens, including Escherichia coli, 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 the 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 attachment 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 modulation 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 changes 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072650-04
Application #
7064798
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Rabadan-Diehl, Cristina
Project Start
2002-12-30
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
4
Fiscal Year
2006
Total Cost
$327,372
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Banadakoppa, M; Chauhan, M S; Havemann, D et al. (2014) Spontaneous abortion is associated with elevated systemic C5a and reduced mRNA of complement inhibitory proteins in placenta. Clin Exp Immunol 177:743-9
Banadakoppa, Manu; Goluszko, Pawel; Liebenthal, Daniel et al. (2014) PI3K/Akt pathway restricts epithelial adhesion of Dr + Escherichia coli by down-regulating the expression of decay accelerating factor. Exp Biol Med (Maywood) 239:581-94
Banadakoppa, Manu; Liebenthal, Daniel; Nowak, David E et al. (2013) Role of transcription factor Sp1 and RNA binding protein HuR in the downregulation of Dr+ Escherichia coli receptor protein decay accelerating factor (DAF or CD55) by nitric oxide. FEBS J 280:840-54
Sathishkumar, K; Balakrishnan, M; Chinnathambi, V et al. (2012) Fetal sex-related dysregulation in testosterone production and their receptor expression in the human placenta with preeclampsia. J Perinatol 32:328-35
Sathishkumar, K; Elkins, Rebekah; Yallampalli, Uma et al. (2012) Protein restriction during pregnancy induces hypertension in adult female rat offspring--influence of oestradiol. Br J Nutr 107:665-73
Banadakoppa, Manu; Goluszko, Pawel; Liebenthal, Daniel et al. (2012) Nitric oxide induces segregation of decay accelerating factor (DAF or CD55) from the membrane lipid-rafts and its internalization in human endometrial cells. Cell Biol Int 36:901-7
Sathishkumar, K; Elkins, Rebekah; Yallampalli, Uma et al. (2011) Fetal programming of adult hypertension in female rat offspring exposed to androgens in utero. Early Hum Dev 87:407-14
Sathishkumar, Kunju; Elkins, Rebekah; Chinnathambi, Vijayakumar et al. (2011) Prenatal testosterone-induced fetal growth restriction is associated with down-regulation of rat placental amino acid transport. Reprod Biol Endocrinol 9:110
Wroblewska-Seniuk, Katarzyna; Nowicki, Stella; Le Bouguénec, Chantal et al. (2011) Maternal/fetal mortality and fetal growth restriction: role of nitric oxide and virulence factors in intrauterine infection in rats. Am J Obstet Gynecol 205:83.e1-7
Sathishkumar, Kunju; Elkins, Rebekah; Yallampalli, Uma et al. (2009) Protein restriction during pregnancy induces hypertension and impairs endothelium-dependent vascular function in adult female offspring. J Vasc Res 46:229-39

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