Supervisor: Dr Amanda Sferruzzi-Perri
Cardiac hypertrophy is defined as an increase in cardiomyocyte size that can be beneficial and adaptive (physiological) or a maladaptive (pathophysiological) phenomenon to compensate for the hemodynamic stress resulting from pressure or volume overloads. Physiological hypertrophy is reversible and occurs during developmental maturation, pregnancy, and exercise without any damaging effects on cardiac function. Relative to the known molecular changes that can occur during exercise-induced cardiac hypertrophy, as well as during pathological cardiac growth, little is known about the molecular mechanisms governing cardiac adaptation during pregnancy.
PI3K-p110α is a critical regulator of growth and function. It is essential for embryonic development and is implicated in regulating heart growth during development, and in response to stimuli. Recent work shows that mice heterozygous for a dominant negative PI3K-p110α (PI3K-p110αD933A/+), display exacerbated pregnancy-related cardiac hypertrophy, even though pre-pregnancy heart weight is similar to wildtype (25% more growth during pregnancy, Sferruzzi-Perri laboratory observations). However, nothing is known about PI3K-p110α in pregnancy-related changes in the heart. Thus a PhD project would determine the significance of PI3K-p110α signalling in pregnancy-related changes in the heart and long-term cardiovascular health. It would determine the impact of p110α inactivity (PI3K-p110αD933A/+) on cardiac function and structure during mouse pregnancy (using high resolution ultrasound, blood pressure measurements, stereology and histology). It would identify the molecular mechanisms governing structural and functional changes by assessing the expression of hypertrophy and contractile function genes and by comparing the transcriptomes of the PI3K-p110α mutant and wildtype hearts. In addition, the project would assess whether exacerbated pregnancy-related cardiac hypertrophy increases the risk of cardiovascular dysfunction in aging PI3K-p110αD933A/+ mice.