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Isolating the Effects of Developmental Hypoxia in Programming Cardiovascular Disease (Dino Giussani)

Supervisor: Professor Dino Giussani

Heart disease is the greatest killer in the world today, affecting 1 in 3 people. We know that the risk of heart disease is determined by a gene-environment interaction and that lifestyle risk factors such as smoking, obesity and a sedentary life promote heart disease. More recently, it has become clear that the environment before birth may be just as, if not more, important in setting the risk of heart disease. However, the mechanisms underlying this gene-early environment interaction are unclear, preventing the design of potential interventional therapy. The most common consequence of an adverse intrauterine environment in complicated pregnancy is a reduction in fetal oxygenation and in nutrition. However, the partial contributions of fetal hypoxia or undernutrition to programming cardiovascular disease are unknown. By using the chick embryo, this PhD project will isolate the direct effects of developmental hypoxia in programming heart disease, determining mechanisms and proposing intervention. The project will test the hypothesis that oxidative stress underlies the molecular basis via which developmental hypoxia alone programmes cardiovascular disease. Using an integrative approach that includes studies of the whole body in vivo (chronically-instrumented preparations and echocardiography), the isolated organ (Langendorff and vessel wire myography), cellular (stereology and histology), molecular (mRNA, protein expression and epigenetic modification), we will determine whether treatment with antioxidants of chick embryos developing under chronic hypoxia prevents the programming of disease. Studies will be conducted in the chick embryo and the adult bird. The project is ideally suited for a BBSRC DTP Studentship, as it fits with training in vulnerable skills, it is highly interdisciplinary and it is timely. The data may hasten translation to relatively simple but novel interventions to treat the onset of cardiovascular disease at its very onset, thereby having a major clinical, economic and social impact on health.

Relevant references

Itani N, Skeffington KL, Beck C, Niu Y, Giussani DA. Melatonin rescues cardiovascular dysfunction during hypoxic development in the chick embryo . J Pineal Res. 2015 Oct 7. doi: 10.1111/jpi.12283.

Giussani DA, Niu Y, Herrera EA, Richter HG, Camm EJ, Thakor AS, Kane AD, Hansell JA, Brain KL, Skeffington KL, Itani N, Wooding FB, Cross CM, Allison BJ. Heart disease link to fetal hypoxia and oxidative stress. Adv Exp Med Biol. 2014;814:77-87. doi: 10.1007/978-1-4939-1031-1_7. Review.

Giussani DA, Davidge ST. Developmental programming of cardiovascular disease by prenatal hypoxia. J Dev Orig Health Dis. 2013 Oct;4(5):328-37.

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