Ph.D - Biomedical Sciences (Anatomy and Reproductive Biology - Cell, Molecular, and Neuroscience)
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ItemThe human fetal membranes, decidua and placenta as paracrine system( 1995)The full characterization of a hormone requires knowledge of its chemical structure and control of its synthesis/cells of origin, its mode of transmission, the localization and structure of its receptor and binding proteins, the activation of its second messengers and its modulation of the transcription of specific genes in specific tissues-its biological effect. The work presented here offers significant insights into two peptide hormones of known structure, prolactin (PRL) and relaxin (RLX), shown by others to be products of the maternal decidua and to transverse the juxtaposed fetal membranes into the amniotic fluid rather than into the systemic circulation. A study of the receptor for PRL by the techniques of Northern analysis, in situ hybridization and immunocytochemistry has shown that the receptor is widely distributed in the maternal-fetal compartment and in the placenta and points to major autocrine and paracrine targets for decidual PRL. A new area of investigation has been opened up by applying the technique of Western blot analysis to separate PRL receptor (PRL-R), related proteins produced at the different sites of translation since, in addition to the classical 95-85 kDa membrane-bound PRL-R, additional species in tissue lysates and in the media of tissue explants have been identified. Further studies may give insights into the processing of the receptor intracellularly and/or lead to the novel demonstration that these proteins are involved in the transport mechanisms necessary, in addition to the PRL-Rs, in the amnion, chorion and decidua to direct the decidua PRL to the fetal compartment rather than to the maternal myometrium and systemic circulation. The presence of a receptor for the hormone RLX in the human chorio-decidua has been confirmed after almost a decade since it was first demonstrated, using chemically synthesized human RLXs H1 and H2 and a new method of labeling which preserves receptor binding activity. The binding of y32P-labeled RLX H2 to chorio-decidua enriched membrane particulate fractions has been optimized. The specificity of the binding of RLX to these particulate fractions and other characteristics of the binding have been completed. Evidence is presented for a single RLX-R target for both of the human RLXs produced in the decidua. The binding of human RLX H1, albeit with a 5 fold lower affinity than RLX H2 provides inferential evidence that the HI RLX gene product is of biological significance. Hence, the results indicate that like PRL, the human RLXs HI and H2, elaborated by the human decidua, have autocrine/paracrine actions within the decidua and the fetal membranes and should stimulate further attempts to isolate and characterize the receptors for the RLXs and to study their distribution within the maternal-fetal compartment. CO-existence of PRL and RLX and their receptors in the maternal-fetal compartment have been linked by the observation here that PRL may complement the role of RLX established by others on the release of specific metalloproteinases targeting the collagen of the extracellular matrix. The modulation of the action of a hormone by changes in the concentration of its receptors, rather than in the tissue concentration of the hormone, has been shown. An increase in the transcription of the PRL-R gene has been demonstrated after normal spontaneous labor and delivery. If a similar increase in the concentration of RLX-R was established, a cascade mechanism for the initiation of the massive collagenolysis associated with and required after the expulsion of the fetus may be established.