Preterm labor is the major cause of perinatal morbidity and mortality and imposes huge financial and emotional burdens upon society. Currently, no treatment exists that significantly reduces morbidity and mortality resulting from preterm labor. Our lack of knowledge of the myometrial events surrounding preterm labor is not surprising given how little we know of the mechanisms controlling normal parturition. Therefore, the central theme of this program is to increase our understanding of the cellular mechanisms that regulate myometrial activity. Four closely-related basic science projects have been assembled and are supported by three core units. These projects will utilize common human and rat tissues and hormonally manipulated rat models of preterm labor. The objectives of the four projects are to determine: (1) The ontogeny of synthesis, transport, endocytosis and degradation of gap junction protein, connexin 43 and the influence of hormonal and pharmacologic manipulation on connexin 43 turnover in myometrium; (2) The ontogeny, quantitation and physiological function of fast sodium channels and the accompanying fast sodium current in myometrium with regard to signal propagation and automaticity and the relationship to sodium/calcium exchange and hence intracellular ionized calcium; (3) The expression, localization, and hormonal regulation of annexins II and VI in myometrium, the role of annexin II in connexin 43 expression and activity and the role of annexin VI in calcium release from the sarcoplasmic reticulum, on the IP3 sensitive calcium channel and on calcium dynamics oligonucleotides antisense to annexin mRNA will be employed in these studies; (4) The mechanisms whereby steroid hormones acting via receptor or membrane-mediated events determine eicosanoid synthesis and action in myometrium in term or preterm labor or following hormonal manipulation. An administrative core serves to allow successful implementation and administration of the program. A clinical core serves to provide human myometrium and blood obtained at term or preterm from patients who are or are not in labor to the four projects in addition to maintaining the requisite patient information. A tissue culture core serves to collect and distribute tissue and provide cultured rat and human myometrial cells to the four projects. Overall, these studies will increase our knowledge of the mechanisms controlling parturition and the comparative changes in preterm labor.
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