Premature birth is a major cause of perinatal mortality and illness in the United States, and delayed or failed labor often requires surgical intervention. These examples emphasize the importance of timely initiation of labor, and the potentially adverse outcomes which may result from interference with uterine function. The onset of labor is accompanied by a dramatic increase in the area and incidence of gap junctions in the myometrium. Gap junctions are the membrane structures believed to mediate direct cell-to-cell transfer of small compounds. These junctions allow rapid transmission of small inorganic ions which propagate action potentials and synchronize contractions of myometrial cells during labor. Many substances, including toxicants, drugs and hormones, are known to affect the formation and function of these junctions in various tissues, and these actions may underline certain physiological and pathological responses. Cell cultures have not been used previously to asses the impact of substances on uterine junctional communication, nor have environmental toxicants been evaluated for potential effects on myometrial cell- cell communication. The hypothesis of the proposed research is that environmental toxicants, drugs, and certain physiological substances may alter cell-cell communication among myometrial cells, and that these effects may be mediated by calcium, cAMP, pH and/or protein phosphorylation. Assuming that communicating junctions are necessary for the onset of labor, this research may improve management of labor, thereby allowing for safer and more successful pregnancy outcome.
The specific aims of the proposed research are to: (1) establish protocols to measure cell-cell communication in myometrial cultures; (2) evaluate the uterine cell line, SK-UT-1, for inhibition of cell-cell communication by substances known to inhibit myometrial gap junction formation, labor or cell-to-cell communication in other cell/test systems; (3) establish cell lines of rat and human myometrium; if this is not possible, then establish procedures for in vitro maintenance of uterine strips from rats and humans; (4) evaluate myometrial cultures for intrinsic levels of cell-cell communication; (5) evaluate potentially hazardous substances, drugs and certain physiological substances for their ability to alter cell-cell communication; (6) investigate mechanisms of modulation of junctional communication in myometrial cultures, focusing on protein phosphorylation, calcium, pH and cAMP involvement.
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