Preterm birth is not only the major cause of infant mortality, but also places the surviving individual at increased risk for significant mental and physical disabilities and major adult diseases. The preterm premature rupture of the fetal membranes (PPROM) is the cause of 30-40% of all preterm births and about 40% of these are due to infection. We have identified the only non-infectious pathway for PPROM to date. In these women with PPROM and no infection, there is increased expression of the relaxin genes and proteins in the decidua and placenta. Relaxin causes increased growth of the fetal membranes via stimulation of IGF-ll and increased degradation of the extracellular matrix (ECM). ? ? We have measured 488 genes in rare PPROM tissues, devoid of many of the usual confounding variables associated with preterm birth and shown relaxin and the expression of 29 other genes altered. From these data, three sets of genes/gene pathways have been chosen for further study: a pathway for development/growth, an inflammatory pathway and two genes whose products alter the structure of the ECM. We will place relaxin into the context of these changes, in order to understand this pathology further. Thus, in Specific Aim 1, we will study the relationships of relaxin to the genes/pathways altered at PPROM, in cell lines, tissue explants and in vivo.
In Specific Aim 2, we will carry out a collaborative study using a rhesus monkey model and give relaxin directly into the amniotic cavity at preterm. The structure of the membranes and the genes/pathways of interest will be studied.
In Specific Aim 3, an in vitro model will be used to study the effects of the rupture on the tissue. This will allow us to distinguish the cause of PPROM from its effect. These changes will then be sought after PPROM in vivo. The combined results will significantly increase our understanding of the non-infectious cause(s) of PPROM.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD024314-16
Application #
7064299
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Ilekis, John V
Project Start
1997-07-01
Project End
2008-09-30
Budget Start
2006-07-01
Budget End
2008-09-30
Support Year
16
Fiscal Year
2006
Total Cost
$299,469
Indirect Cost
Name
University of Hawaii
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822
Horton, J S; Yamamoto, S Y; Bryant-Greenwood, G D (2012) Relaxin augments the inflammatory IL6 response in the choriodecidua. Placenta 33:399-407
Horton, J S; Yamamoto, S Y; Bryant-Greenwood, G D (2011) Relaxin modulates proinflammatory cytokine secretion from human decidual macrophages. Biol Reprod 85:788-97
Bryant-Greenwood, G D; Yamamoto, S Y; Sadowsky, D W et al. (2009) Relaxin stimulates interleukin-6 and interleukin-8 secretion from the extraplacental chorionic cytotrophoblast. Placenta 30:599-606
Kern, AndrĂ¡s; Bryant-Greenwood, Gillian D (2009) Characterization of relaxin receptor (RXFP1) desensitization and internalization in primary human decidual cells and RXFP1-transfected HEK293 cells. Endocrinology 150:2419-28
Kern, Andras; Bryant-Greenwood, Gillian D (2009) Mechanisms of relaxin receptor (LGR7/RXFP1) expression and function. Ann N Y Acad Sci 1160:60-6
Horton, Jaime S; Yamamoto, Sandra Y; Bryant-Greenwood, Gillian D (2009) Identification of relaxin-responsive cells in the human choriodecidua at term. Ann N Y Acad Sci 1160:136-7
Kern, Andras; Hubbard, Daniela; Amano, Aaron et al. (2008) Cloning, expression, and functional characterization of relaxin receptor (leucine-rich repeat-containing g protein-coupled receptor 7) splice variants from human fetal membranes. Endocrinology 149:1277-94
Kendal-Wright, C E; Hubbard, D; Bryant-Greenwood, G D (2008) Chronic stretching of amniotic epithelial cells increases pre-B cell colony-enhancing factor (PBEF/visfatin) expression and protects them from apoptosis. Placenta 29:255-65
Bryant-Greenwood, Gillian D; Kern, Andras; Yamamoto, Sandra Y et al. (2007) Relaxin and the human fetal membranes. Reprod Sci 14:42-5
Kendal, C E; Bryant-Greenwood, G D (2007) Pre-B-cell colony-enhancing factor (PBEF/Visfatin) gene expression is modulated by NF-kappaB and AP-1 in human amniotic epithelial cells. Placenta 28:305-14

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