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Title: Modelling the contribution of hormonal and inflammatory pathways to term and preterm labour in the mouse
Author: Migale, Roberta
ISNI:       0000 0004 6059 2036
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2016
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Labour onset results from a complex interplay between hormonal and inflammatory signals. Untimely activation of these pathways can cause preterm labour (PTL) and premature birth (< 37 weeks of gestation), the primary cause of infant mortality. Throughout gestation, uterine quiescence is maintained by progesterone and its withdrawal at term induces pro-labour genes and activation of uterine contractions. Infection and inflammation are frequently associated with PTL. Recognition of bacteria by the maternal innate immune system involves activation of nuclear factor kappa-B (NFκB) and activator protein-1 (AP-1), which regulate inflammatory and pro-labour genes. The aim of this thesis was to determine the contribution of inflammatory and hormonal pathways to parturition in murine models by comparing molecular changes in myometrium throughout term gestation, PTL induced by lipopolysaccharide (LPS; inflammation-induced PTL), and RU486-induced PTL by progesterone withdrawal (non-inflammatory PTL). Term gestation was shown to involve sequential activation of NFκB and AP-1. Different LPS serotypes induced heterogeneous maternal and fetal responses in the LPS-induced PTL model. LPS O111:B4 caused the most severe phenotype of PTL within 7h and total fetal demise. This involved JNK/AP-1-mediated activation of uterine inflammation, without NFκB activation. TLR-4 ablation rescued this phenotype and JNK inhibition delayed PTL. RU486 caused PTL without modulation of inflammatory pathways. RNA-Seq was used to characterize dynamic uterine transcriptome changes antecedent to term labour or PTL (RU486 or LPS-induced). Strong similarity was observed within term gestation and RU486-induced PTL transcriptomes, while the LPS model involved distinctive inflammatory gene changes. Positive correlation was found between human and murine transcriptomes. This thesis shows that LPS-induced inflammation can override repressive effects of progesterone on pro-labour genes while abrogation of progesterone signalling prompts PTL without inflammatory gene activation. These data support the paradigm of a common terminal pathway of labour yet provides new evidence that inflammatory gene activation is not necessary for labour.
Supervisor: Bennett, Phillip ; MacIntyre, David Sponsor: Genesis Research Trust ; Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral