This proposal will elucidate how the human pregnant uterus coordinates myometrial cell function with uterine contractility. Knowledge gained from this work will define the factors responsible for the coordination, initiation, and maintenance of labor. These issues are intimately associated with preterm labor, postdates pregnancy, and dysfunctional labor, which correlate directly with prematurity, fetal distress, and cesarean section rates. Improved understanding of uterine contractility will potentially allow treatments of an abnormality of labor to be directed towards the underlying physiological abnormality. We have recently developed the initial form of a hypothesis that specifies how the uterine cells communicate in human labor. This model incorporates global (throughout the entire uterus) with local mechanisms. The essence of this model is that organ-level communication is by action potential propagation, but the signal responsible for initiating contraction of each cell is carried by intercellular calcium waves. This hypothesis is therefore called the action potential - calcium wave hypothesis (AP-wave hypothesis). The purpose of this research is to test the foundation and formulation of the AP-wave hypothesis and to modify it when shortcomings are identified. The evolving form of this hypothesis will hopefully allow clinicians to trace specific clinical parameters of labor (such as strength and frequency of uterine contractions) back to cellular mechanisms. As a result, specific abnormalities of labor (poor spacing of contractions, abnormal response to oxytocin, elevated baseline pressure, and many others) would then be able to be correlated with specific cellular functions. This knowledge would provide the scientific basis for the selection of a particular therapy for a particular abnormality of labor. We propose a combination of techniques (structural studies of tissue, confocal microscopy, electrophysiology and calcium dye imaging) with a goal of understanding calcium metabolism and signal transmission through tissue. At the conclusion of this project we will have an improved understanding of the functional unit of the human pregnant uterus, which will provide the basis for education, research, and application of basic science knowledge to clinical medicine.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD036373-03
Application #
6343215
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Ilekis, John V
Project Start
1999-01-01
Project End
2003-12-31
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
3
Fiscal Year
2001
Total Cost
$202,294
Indirect Cost
Name
Medical University of South Carolina
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Young, Roger C; Zhang, PeiSheng (2005) Inhibition of in vitro contractions of human myometrium by mibefradil, a T-type calcium channel blocker: support for a model using excitation-contraction coupling, and autocrine and paracrine signaling mechanisms. J Soc Gynecol Investig 12:e7-12
Young, Roger C; Zhang, PeiSheng (2004) Tissue-level bioelectrical signals as the trigger for uterine contractions in human pregnancy. J Soc Gynecol Investig 11:478-82
Young, Roger C; Zhang, PeiSheng (2004) Functional separation of deep cytoplasmic calcium from subplasmalemmal space calcium in cultured human uterine smooth muscle cells. Cell Calcium 36:11-7
Young, Roger C; Schumann, Ralph; Zhang, Peisheng (2003) Three-dimensional culture of human uterine smooth muscle myocytes on a resorbable scaffolding. Tissue Eng 9:451-9
Robinson, Christopher; Schumann, Ralph; Zhang, Peisheng et al. (2003) Oxytocin-induced desensitization of the oxytocin receptor. Am J Obstet Gynecol 188:497-502
Young, Roger C; Schumann, Ralph; Zhang, Peisheng (2002) The signaling mechanisms of long distance intercellular calcium waves (far waves) in cultured human uterine myocytes. J Muscle Res Cell Motil 23:279-84
Young, R C; Zhang, P (2001) The mechanism of propagation of intracellular calcium waves in cultured human uterine myocytes. Am J Obstet Gynecol 184:1228-34
Landen Jr, C N; Zhang, P; Young, R C (2001) Differing mechanisms of inhibition of calcium increases in human uterine myocytes by indomethacin and nimesulide. Am J Obstet Gynecol 184:1100-3
Young, R C; Schumann, R; Zhang, P (2001) Intracellular calcium gradients in cultured human uterine smooth muscle: a functionally important subplasmalemmal space. Cell Calcium 29:183-9
Young, R C; Schumann, R; Zhang, P (2001) Nifedipine block of capacitative calcium entry in cultured human uterine smooth-muscle cells. J Soc Gynecol Investig 8:210-5

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