Our understanding of uterine function at term remains poor while both preterm labor and uterine dysfunction in term labor are significant clinical problems. There is increasing evidence for a role of Na/+ channels in uterine contraction including the recent cloning in the Tamkun laboratory of a novel voltage gated sodium channel (mNav2.3) which is up- regulated in myometrium during pregnancy. The broad, long term objectives of this proposed research is to gain an understanding of the physiological role that the Nav2.3 channel plays in controlling uterine contraction. Specifically, this proposal seeks first to compare Na/+ current density and mNav2.3 expression in mouse uterine myocytes at different times in gestation using the patch clamp technique and immunohistochemical assays. Second, in order to determine to determine if the Na/+ current observed in uterine myocytes is due to expression of the Nav2.3 gene, antisense strategies design to inhibit expression of mNav2.3 protein will be used to knock-down Na/+ channel current. Finally, heterologous expression using adenoviral vectors to deliver DNA encoding the Nav2.3 channel in native uterine myocytes from non-pregnant mice will be performed. The experiments outlined in this proposal will determine if the Nav.23 protein underlies the observed Na/+ current and will help elucidate its role in the regulation of uterine contraction at term. While pre-term labor is a major health problem given the risk it carries with respect to birth defects and costs associated with premature delivery, a better understanding of the regulation of uterine contraction can only improve our ability to pharmacologically manage this problem.
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