The long-range goals of the studies supported by this grant over the years have been to define the mechanisms by which the pregnant and post-partum uterus regulates the metabolism of its principle connective tissue protein, collagen. This protein is absolutely required by the uterus for the structural integrity of the organ during pregnancy. Thus it is necessary to precisely regulate the amount and distribution of collagen in the tissue during gestation. After delivery, the protein is degraded during the rapid involution of the uterus occurring in all mammals. The degradation of collagen requires the action of a specific enzyme, interstitial collagenase, whose function it is to catalyze the cleavage in collagen which initiates the enzymatic degradation of the interstitial collagens. Our approach to these goals has been to obtain, in pure form, the molecules which are required for this process to occur in an orderly fashion, and to study the mechanisms by which they are controlled. Our studies have concentrated on the regulation of the gene for interstitial collagenase by the indoleamine serotonin. We have defined a major, new role for serotonin in myometrial smooth muscle cells: that of an obligatory activator of the gene for interstitial collagenase. In addition, we have identified serotonin as a multifunctional regulator of gene activation in the uterine myometrium. To date we have identified some fifteen genes regulated by serotonin in this cell. Of particular interest is the serotonin-dependent activation of interleukin-1 in these cells. We have shown that the induction of this cytokine is crucially required for the up-regulation of the interstitial gene. In the following years we propose to further elucidate the role of serotonin in the myometrial smooth muscle cell, to identify both the genes which are regulated as well as the mechanisms by which serotonin modulates the expression of these genes. Thus, we wish to examine specific elements in the promoters in a number of these genes which are required for serotonin- dependent gene regulation, in both positive and negative directions. It is our hope that, by defining the molecules involved in serotonin-mediated pathways, as well as the way in which their biological activity is regulated, normal pregnancy, labor and perinatal homeostasis can be better understood and more rationally managed. Moreover, it is anticipated that this information can also be applied to complicated pregnancies, in which fetal health may be endangered by uterine dysfunction.
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