Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.682879
Title: 11ß-HSD2 dependent and independent signalling pathways in trophoblast biology and glucocorticoid responsiveness
Author: Hein, Anna Caroline
ISNI:       0000 0004 5915 2746
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2015
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Abstract:
The placenta is the interface between the mother and the fetus fulilling important roles such as nutrient transfer, hormone production and barrier functions. Pathological conditions associated with maternal stress during pregnancy can cause placental adaptations which possibly affect fetal health and might lead to long-term effects in later life. The placenta contains an autonomous endocrine system which consists of hormones such as corticotropin-releasing hormone (CRH) and cortisol (the human glucocorticoid) controlling stress responses. Exposure of the fetus and placenta to glucocorticoids (GCs) is finetuned by CRH. The presence of a GC barrier also modulates GC availability. The main component of this GC barrier is the enzyme 11ß-HSD2 which catalyzes active cortisol into cortisone. Expression of this enzyme is decreased in placental diseases such as pre-eclampsia and intrauterine growth restriction (IUGR). This might be associated with elevated levels of trophoblast apoptosis and disturbances of trophoblast differentiation found in pregnancy-related disorders. Very little is known about the specific role of this enzyme and related pathways in placental apoptosis, differentiation, endocrine capacity and the expression of molecules involved in the stress response and glucocorticoid action. These potential effects were investigated in this thesis by using the placental explant culture and the choriocarcinoma BeWo cellular model. Furthermore, the capacity of GCs to regulate transcriptional events in BeWo cells was explored. My results show that CRH treatment and activation of TLR4 have modulating effects on placental hCG production in placental explants. Moreover, the enzyme 11ß-HSD2 seems to be involved in the homeostasis of placental differentiation and apoptotic processes, the maintenance of hCG and progesterone secretion and it might limit overactivation of CRH receptors and CRH secretion. GC insensitivity was identified in the BeWo cells and it appears that in these cells the cAMP pathway is the predominant pathway in regulating GC-responsive genes. Through a series of reporter-gene-assays my results suggest that transfection of exogenous GRα restores the BeWo cell sensitivity to GCs without affecting BeWo cell turnover and hormone secretion. In conclusion, placental CRH and 11ß-HSD2 expression appear to play an important role in the maintenance of placental endocrine function. GCs on the other hand did not have strong regulatory effects in the BeWo cells suggesting a unique mechanism through which trophoblast cells become insensitive to local glucocorticoid action.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.682879  DOI: Not available
Keywords: RC Internal medicine
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