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Centre for Trophoblast Research

 

Project

Project Title

 

Maternal Obesity: Translatable Programmed Cardiovascular

Dysfunction in Offspring

Project description

Maternal obesity during pregnancy is an alarming health care issue with short- and long-term detrimental consequences for mother and child. In her last report, as Chief Medical Officer, Dame Sally Davies highlighted that over half of women in the UK are over-weight or obese during pregnancy. She stressed that a focus on the health of the pregnant woman and of her offspring and interventions to improve it offers a new and important opportunity to ensure the wellbeing of mothers and their children. The proposed PhD project addresses this issue directly using a well characterised sheep model of maternal obesity during pregnancy. It will define mechanisms by which obesity during pregnancy influences the risk of heart disease in the offspring and provide invaluable information on what interventions during pregnancy can prevent this effect. In contrast to rodents, such as mice and rats, which are born highly immature, in sheep and humans, the fetal heart and blood vessels mature their structure and function at similar rates during development. Therefore, sheep are an ideal animal model to address these questions and make the research more relevant to the human clinical situation.

 

Goal of research

This project will mimic the human situation of obesity during pregnancy in sheep and determine how maternal obesity can harm the baby’s heart and circulation before birth. It will test a specific antioxidant drug as potential treatment during obese pregnancy to prevent this. The project will take advantage of the sheep model to test fetal and adult cardiovascular function in vivo under basal and stimulated conditions, experiments that cannot be done in other species. Cardiovascular functional outcomes will be linked to molecular pathways, including changes in oxidative stress signalling and miRNA dysregulation.

 

Potential benefit of research

The results may lead to the design of clinical therapies to combat the ill effects of maternal obesity on the baby’s heart and circulation to dimmish the risk of heart problems in later life. Cardiovascular disease is the greatest killer in the UK today and early origins of cardiovascular disease, such as those imposed by maternal obesity during pregnancy on the unborn child, contribute to this. Therefore, the work offers robust plans designed to deliver realistic interventions to improve population health and improve the quality of life not only in obese women but also their children, thereby having a major clinical, economic and societal impact on health.

 

Timing, Collaborations and Grand Challenges

This PhD will be coupled to a programme of work recently funded by the MRC, which will start in March 2022. Therefore, the timing of the studentship is optimal. The proposed PhD combines the expertise of two CTR PIs. Dino Giussani is an expert in fetal cardiovascular function. Sue Ozanne is an expert in molecular biology and epigenetics.

The project addresses one of the CTR Grand Challenges directly by helping us decipher how maternal obesity, as an environmental cue, can cause pathological complications of human pregnancy, and how this knowledge can be translated into novel preventative interventions.

References

Examples of cardiovascular expertise in sheep:

1. Botting KJ, Skeffington KL, Niu Y, Allison BJ, Brain KL, Itani N, Beck C, Logan A, Murray AJ, Murphy MP, Giussani DA. Translatable mitochondria-targeted protection against programmed cardiovascular dysfunction. Sci Adv. 2020;6(34):eabb1929;

2. Allison BJ, Brain KL, Niu Y, Kane AD, Herrera EA, Thakor AS, Botting KJ, Cross CM, Itani N, Shaw CJ, Skeffington KL, Beck C, Giussani DA. Altered Cardiovascular Defense to Hypotensive Stress in the Chronically Hypoxic Fetus. Hypertension. 2020;76(4):1195-1207.

3. Brain KL, Allison BJ, Niu Y, Cross CM, Itani N, Kane AD, Herrera EA, Skeffington KL, Botting KJ, Giussani DA. Intervention against hypertension in the next generationprogrammed by developmental hypoxia. PLoS Biol. 2019;17(1):e2006552.

 

Examples of Giussani-Ozanne collaborations using molecular expertise:

4. Spiroski AM, Niu Y, Nicholas LM, Austin-Williams S, Camm EJ, Sutherland MR, Ashmore TJ, Skeffington KL, Logan A, Ozanne SE, Murphy MP, Giussani DA. Mitochondria antioxidant protection against cardiovascular dysfunction programmed by early-onset gestational hypoxia. FASEB J. 2021;35(5):e21446.

5. Teulings NEWD, Garrud TAC, Niu Y, Skeffington KL, Beck C, Itani N, Conlon FG, Botting KJ, Nicholas LM, Ashmore TJ, Blackmore HL, Tong W, Camm EJ, Derks JB, Logan A, Murphy MP, Ozanne SE, Giussani DA. Isolating adverse effects of glucocorticoids on the embryonic cardiovascular system. FASEB J. 2020;34(7):9664-9677.

Candidate background (please note any required background or selection criteria)

The PhD candidate will have good knowledge of cardiovascular physiology, pregnancy and developmental origins of health and disease.