The long-range goal of this clinically-based research project is to define the evolution of three processes (related at the regulatory level) that are important to human parturition. First, the relationship between inflammation and parturition will be explored further. There is a widely- held view that """"""""silent"""""""" infection of intrauterine tissues is a relatively common cause of preterm labor; but, the data we have assembled are not supportive of this premise. We suggest that the question to be addressed is as follows: Does inflammation, by way of mediators of the inflammatory response, give rise to the initiation of parturition at term or preterm; or rather, is it that labor begets inflammation? Because of the urgency to determine the causes of and means for preventing preterm labor, the conduct of this research is high on our clinical parturition research agenda. The tissue site of origin of inflammatory mediators that enter amniotic fluid at parturition will be defined and the anatomic limits of the inflammatory response in decidua parietalis and fetal membranes during labor at term and preterm will be mapped. Second, the natural order of appearance of uterine markers of phase 1 of parturition, i.e., uterine preparedness for labor will be determined. To do so, a large number of myometrial tissue samples (obtained late in pregnancy) will be evaluated for levels of oxytocin receptor and mRNAs for connexin43, parathyroid hormone-related protein(PTH- Rp), calbindin-9K, transforming growth factor-betas (TGF-beta1,2,3), preproendothelin (ET-1), and ETA,beta receptors. Third, the evolution and potential abnormalities of the ET-1/enkephalinase-PTH-Rp system of the fetal membranes will be evaluated. ET-1 (a potent vasoconstrictor) and PTH-Rp (a vasorelaxant) are produced in amnion, as is enkephalinase [membrane metalloendopeptidase (EC 3.4.24.11)], which degrades endothelins. Placental amnion is directly contiguous with fetal chorionic vessels that traverse the fetal surface of the placenta on the chorionic plate. Therefore, the possibility of an involvement of this system in the modulation of fetal chorionic, villous, and umbilical vessel tone is very alluring. The molecular regulation of the ET-1/enkephalinase-PTH-Rp system appears to be similar , in many regards, to that of myometrial phase 1 processes. And, inflammation is important in the expression of selected components of both systems; e.g., IL-1beta acts on amnion cells to induce preproET-1 and PTH-Rp gene expression and protein secretion. TGF-beta acts to induce PTH-Rp and preproET-1 in amnion and myometrium but to decrease enkephalinase in amnion and decidua. The findings of each aim of these clinical studies are pertinent to the research described in Project II, which is designed to define the biomolecular regulation of these processes. We are fortunate to have a very large obstetric population of cooperative women volunteers who are highly motivated to participate in clinical research to solve one of the major health hazards of the world today, namely, preterm birth.
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