The long term goals of this application are to define the mechanisms by which the pregnant and post-partum uterus regulates the metabolism of 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 general involution of the uterus which occurs in all mammals. The degradation of collagen in the uterus requires the action of a specific collagenase whose function it is to catalyze the crucial cleavages in collagen which initiate the process by which the protein is removed from the extracellular matrix. The physiologic processes by which the appearance of these molecules in the uterus is regulated will be studied in cell culture systems and in explant cultures. The nature of the mechanisms whereby collagenase production and activity can be induced, modulated in situ, and terminated when no longer required, will be studied. Such mechanisms involve the physiologic activities of important gestational hormones such as progesterone and the glucocorticoids, as well as a newly re-discovered hormone, serotonin. The results of these investigations should provide fundamental information regarding the mechanisms by which collagen degradation is accomplished in the uterus. It is hoped that by understanding the molecules involved in these processes and the way in which their biological activity is regulated, normal pregnancy and labor can be better understood and more rationally managed.
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