Preterm delivery occurs in up to 10% of births and accounts for 75% of neonatal deaths. A greater understanding of the mechanisms of contractile quiescence during normal pregnancy is sorely needed. The general aim of this proposal is to test the hypothesis that basal thin (actin) and thick (myosin) filament regulatory mechanisms are chronically altered during normal and abnormal pregnancy and labor.
The specific aims are: (1) To investigate the hypothesis that changes in either the protein levels or phosphorylation levels of the actin binding protein, Caldesmon (CaD) contribute to gestation dependent contractility changes in both a timed pregnant rat model and in human tissue samples; (2) To investigate the hypothesis that changes in Extracellular Regulated Kinase (ERK1/2) signaling contribute to changes: (a) in CaD activity; and/or (b) in the contractility of myometrium during pregnancy and labor in the rat and human; (3) To investigate the hypothesis that regulation of Myosin Phosphatase is involved in gestation-dependent changes in contractility in the rat and human; and (4) To investigate the hypothesis that coordination of signal transduction that leads to gestation-dependent changes in contractility is, at least in part, mediated by the action of the scaffolding protein, caveolin. Because of the limited supply of human tissue, a timed rat model will be used for the detailed mapping of signaling pathways and the planned in vivo drug studies. However, human samples will be collected in parallel and, on a longer time base, will be used to test critical results obtained with the rat tissue. A multidisciplinary approach will be used, combining functional assessment of contractility, biochemical measurements, quantitative confocal microscopy, organ culture, antisense experiments, and in vivo drug treatment to test the above hypotheses. It is hoped that if novel mechanisms can be identified and defined, the pathways involved will represent new potential targets for therapeutic intervention in cases of preterm and dysfunctional labor.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD043054-05
Application #
7253372
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Ilekis, John V
Project Start
2003-08-18
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2009-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$317,052
Indirect Cost
Name
Boston Biomedical Research Institute
Department
Type
DUNS #
058893371
City
Watertown
State
MA
Country
United States
Zip Code
02472
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Gangopadhyay, Samudra S; Kengni, Edouard; Appel, Sarah et al. (2009) Smooth muscle archvillin is an ERK scaffolding protein. J Biol Chem 284:17607-15
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Gangopadhyay, Samudra S; Gallant, Cynthia; Sundberg, Eric J et al. (2008) Regulation of Ca2+/calmodulin kinase II by a small C-terminal domain phosphatase. Biochem J 412:507-16
Wu, X; Morgan, K G; Jones, C J et al. (2008) Myometrial mechanoadaptation during pregnancy: implications for smooth muscle plasticity and remodelling. J Cell Mol Med 12:1360-73
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Taggart, Michael J; Morgan, Kathleen G (2007) Regulation of the uterine contractile apparatus and cytoskeleton. Semin Cell Dev Biol 18:296-304
Li, Yunping; Gallant, Cynthia; Malek, Sabah et al. (2007) Focal adhesion signaling is required for myometrial ERK activation and contractile phenotype switch before labor. J Cell Biochem 100:129-40
Marganski, William A; Gangopadhyay, Samudra S; Je, Hyun-Dong et al. (2005) Targeting of a novel Ca+2/calmodulin-dependent protein kinase II is essential for extracellular signal-regulated kinase-mediated signaling in differentiated smooth muscle cells. Circ Res 97:541-9

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