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Project |
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Project Title |
Understanding mechanisms underlying the impact of metformin on placental, fetal and maternal health |
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Project description The growing prevalence of obesity worldwide means that in many populations at least 50% of women are overweight or obese at the start of pregnancy. Obesity is a major risk factor for the development of gestational diabetes mellitus (GDM), which affects approximately 1in 7 pregnancies globally. If untreated, maternal hyperglycaemia leads to fetal hyperglycaemia and associated metabolic risks, including fetal over-growth. GDM treatments focus on controlling maternal glycaemia to reduce risk of perinatal complications including stillbirth. Metformin, a biguanide drug, effectively controls maternal glycaemia in human trials (Tarry-Adkins et al 2020) and is a first line drug therapy for GDM in many national guidelines. We can replicate these findings in our established mouse model of maternal diet-induced obesity (Hufnagel et al 2021). Evidence suggests other potential beneficial effects of metformin treatment during pregnancy, including reducing the risk of pre-eclampsia (Tarry-Adkins et al 2021), which is supported by emerging data from clinical trials. We have recently shown that metformin reduces the elevated level of sFlt (used as a biomarker for pre-eclampsia in humans) in our mouse model of maternal diet-induced obesity (Hufnagel et al 2021). Hence there is rapidly increasing international interest in using metformin as drug therapy in pregnancy. However, metformin freely crosses the placenta and rapidly reaches similar or higher levels in the fetal circulation compared to the mother. Metformin therefore has the potential to have direct effects on placental and fetal tissues. Therefore, despite the beneficial effects of metformin on maternal physiology, increasing evidence including that from our own labs, suggests that fetal exposure to metformin could have long-term (and potentially sex-specific) effects on offspring health, including increased adiposity (Schoonejans et al 2021). Despite its widespread use, the mechanisms underlying the action of metformin are poorly understood, especially at the maternal-placental-fetal interface. This project will directly address this urgent knowledge deficit using our established methodology for human trophoblast culture and our well-characterised mouse model of maternal diet-induced obesity (De Barros Mucci et al 2020). Three important questions will be addressed:
The student will obtain training in a wide variety of experimental techniques at multiple levels – physiological (e.g. mouse ultrasonography), cellular (trophoblast isolation and culture), and molecular (RNAseq), as well as data management and data analysis. The results of this project, as well as providing import scientific insights in an under-explored area of biology, will have a direct pathway to clinical impact in maternal and child health worldwide. |
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References Tarry-Adkins JL, Aiken CE & Ozanne SE (2020) Comparative impact of pharmacological treatments for gestational diabetes on neonatal anthropometry independent of maternal glycaemic control: a systematic review and meta-analysis. PLoS Medicine 17(5): e1003126
Hufnagel A, Fernandez-Twinn DS, Blackmore HL, Ashmore TJ, Heaton RA, Jenkins B. Koulman A, Hargreaves IP, Aiken CE & Ozanne SE (2021) Maternal but not fetoplacental health can be improved by metformin in a murine diet-induced model of maternal obesity and glucose intolerance. J Physiol (in press)
Tarry-Adkins JL, Ozanne SE & Aiken CE (2021) Impact of metformin treatment during pregnancy on maternal outcomes: a systematic review/meta-analysis. Scientific Reports 11: 9240.
Schoonejans JM, Blackmore HL, Ashmore TJ, Aiken CJ, Fernandez-Twinn DS & Ozanne SE (2021) Maternal metformin intervention during obese glucose intolerant pregnancy affects adiposity in young adult mouse offspring in a sex-specific manner. International Journal of Molecular Sciences 22:8104
De Barros Mucci D, Kusinski LC, Wilsmore P, Loche E, Pantaleao LC, Ashmore TJ, Blackmore HL, Fernandez-Twinn DS, Carmo MDGTD & Ozanne SE (2020) Impact of maternal obesity on placental transcriptome and morphology associated with fetal growth restriction in mice. Int J Obes. 44:1087-1096 |
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Candidate background |
Degree in a relevant biological science such as physiology, pharmacology or biochemistry |