- Zaccolo Group Research Group
Marcella D. Brescia
Cardiac cyclic nucleotide signalling
I completed my undergraduate degree in Biomedical Sciences at the Universidade FUMEC, in Brazil in 2013 after having spent 1 year as a visiting student at the University of Oxford. Later on the same year I started my doctorate degree at DPAG, University of Oxford, as part of Manuela Zaccolo's group.
My research focuses on understanding the role of the compartmentalisation of cyclic nucleotides signalling in the cardiomyopathy associated to Duchenne Muscular Dystrophy (DMD).
Duchenne muscular dystrophy (DMD), the most frequent muscular dystrophy, is caused by mutations in the dystrophin gene resulting in the absence of dystrophin. Loss of cardiac dystrophin eventually leads to dilated cardiomyopathy and congestive heart failure in at least 20% of patients. Previous studies have shown that inhibition of the cGMP-degrading PDE5 improves cardiac contractility, energy metabolism and cardiac myocyte integrity in the DMD mouse model mdx, suggesting that defective cGMP signalling within the cardiomyocytes may play a role in the pathogenesis of the cardiomyopathy associated with dystrophin deficiency.
My DPhil project tests this hypothesis using real time imaging of FRET-based reporters and analysis of cyclic nucleotides, cAMP and cGMP, signals in different subcellular compartments such as plasma membrane, mitochondria and cytosol in control and MDX neonatal and adult mouse cardiomyocytes. I also explore the importance of these local signals in the regulation of cardiac function. Specifically, the response of MDX myocytes to the application of tension and the measurement of the force of contraction of a single isolated cardiomyocyte in combination with real time imaging of CN.
This project is not only relevant to the cardiac disease related to DMD but also other cardiovascular conditions and allows the understanding of the cyclic nucleotides, especially cGMP, in the heart as never before.
Targeted cGMP FRET sensors
cGMP FRET sensors targeted to the plasma membrane (PM) and outer mitochondria membrane (OMM) in neonatal cardiac myocytes.
Adult cardiomyocyte expressing cytosolic FRET sensor and FRET change graph with single wavelength intensity and ratio.
Force of contraction and contractility measurement of adult mouse cardiomyocytes under stretch.