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.
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