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Final Report Summary - ROLROS (Mitochondrial deficiency and cardiomyopathy. Role of Reactive Oxygen Species)

Mitochondrial deficiency and cardiomyopathy: Role of Reactive Oxygen species.

The main objectives of the proposal were:

Aim 1: Study of the different signalling pathways described to operate in cardiovascular diseases in vitro in cells carrying mtDNA mutation
• Aim1.1 Study of ROS dependent signalling pathways in ES cells carrying mtDNA mutations
• Aim1.2 Study of PKA/PKC signalling pathways in ES cells carrying mtDNA mutations
• Aim1.3 Study of the predisposition of different mitochondrial haplogropus in developing cardiovascular diseases.
Aim 2: Exploration of the signalling pathways in primary cardiomyocytes or in induced pluripotent stem cells derived from patients (iPSC). Study of potential differentiation into cardiac cells.
• Aim2.1 Exploration of the signalling pathways in primary mouse cardiomyocytes or in induced pluripotent stem cells derived from patients (iPSC).
• Aim2.2 Study of potential differentiation of the iPSC cells into cardiac cells
Aim 3: Study of the most relevant signalling pathways found to be active in aim1 and aim2 in vivo in mitochondrial transgenic mice.
During the four-year duration of the project I have been working on the three aims simultaneously
After the completion of the project, there are still several open research lines that will be continued in the near future. I am currently working on pinpointing in the in vivo model elucidating the role of calcium upon ISO stress using C57 and OMA1 KO mice. On the other hand, I am establishing the DTA transgenic colony for future experiments of in vivo cardiac differentiation of mES. Finally, I am working in the cardiac differentiation of iPSC that will be followed by transmitochodrial iPSC generation.
Overall I think that the initial proposal with the acronym ROLROS, trying to explicate the role of ROS and mitochondrial function in the context of cardiac function, has achieved its main goals. I have been able to show how ROS is a critical signalling molecule in the different scenarios proposed: i) in vitro differentiation of mES in cardiomyocytes (Aim1), ii) metabolic adaptation and triggering of metabolic switch in neonatal cardiomyocytes (Aim 2) and iii) in vivo in three independent experimental models of heart failure as initiator of a signalling cascade that ultimately leads to cardiomyocyte death (Aim 3). Moreover, in the latter aim, I have worked with diverse mouse models affecting mitochondrial function to a different extend. Based on the proof of principle experiments performed in the first two years of the project, I have been able to identify genotypes more susceptible to cardiac damage and, in particular one model, which show cardioprotection for every cardiac stress assessed. Based on these results, I could ascribe a new putative target protein to treat cardiovascular disease.

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