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|Title:||A novel intervention strategy to prevent intrauterine growth restriction|
|School/Discipline:||Adelaide Medical School|
|Abstract:||Intrauterine growth restriction (IUGR) increases risks of perinatal death >5-fold, and has lifelong adverse effects on health. There is currently no treatment to prevent or cure IUGR, although animal studies have shown promising effects of maternal growth hormone (GH) treatment on fetal and placental growth. The overall aim of this project was to test a novel approach to stimulate the mother’s own production of GH, to promote placental function and fetal growth in normal and IUGR pregnancies, and hence develop a therapy to prevent IUGR which is acceptable to patients. My first aim was to investigate whether the abundance or activation of the GH secratagogue, ghrelin, increased during pregnancy or in response to dietary supplementation with octanoic acid, which is required for activation (acylation) of ghrelin. Maternal circulating total and acyl-ghrelin and GH profiles were measured in late pregnant mice and in aged-matched non-pregnant females, fed a diet supplemented with octanoic or palmitic (control) acid. However, dietary supplementation did not increase the activation of ghrelin in female mice, whilst the pregnancy-associated increase in maternal GH secretion occurred without elevated circulating acyl-ghrelin concentrations. The second aim was to develop a novel method to measure placental function, a major determinant of fetal growth, using non-radioactive tracers in mice. A dye containing fluorescently-labelled glucose was injected into pregnant dams near term, and its maternal, placental and fetal uptake were characterised. Although the results indicated that this tracer was not specific for placental glucose uptake, its uptake provided a good indication of overall placental function and fetal nutrient uptake. Lastly, in order to test potential interventions, a murine model of IUGR in multiple pregnancies was established. Mouse pregnancies were generated by transferring variable numbers of embryos into pseudo-pregnant mice, generating litters with varying degrees of maternal constraint near term. Fetuses from the largest litters were ~25% lighter as well as thinner and with evidence of brain-sparing, compared to fetuses from smaller litters. Interestingly, the relationship between viable litter size and fetal weight differed between sexes, such that fetal weights of males, but not females, correlated negatively with litter size. However, this sex difference was not explained by morphological and functional changes in the placenta. The results of this experiment suggested that male fetuses grew as fast as permitted by nutrient supply, whereas the female maintained placental reserve capacity. This strategy, likely reflecting sex-specific gene expression, would be expected to place the male fetus at greater risk of death in the face of any additional intrauterine stressors. In conclusion, the dietary supplementation trialled in this project did not promote fetal growth in normal pregnancies or stimulate responses in the mother that would promote fetal growth in growth restricted pregnancies. However, this project has generated valuable new tools to help investigate and ultimately address the major clinical challenge of poor growth before birth. The development and optimisation of this IUGR model will now allow us to combine genetic models in mice with testing of intervention strategies to prevent IUGR due to chronic restriction.|
|Dissertation Note:||Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2020|
|Provenance:||This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals|
|Appears in Collections:||Research Theses|
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