ROLROS · Mitochondrial deficiency and cardiomyopathy. Role of Reactive Oxygen Species
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2012-04-02 → 2016-04-01
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-CIG
Линиите свързват координатора с партньорите.
Накратко на български
Митохондриалните дефицити и реактивните кислородни форми се анализират чрез проучване на клетки с мутации в ДНК на митохондриите. Това помага за разбирането на механизмите, които водят до развитието на сърдечни заболявания.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Mitochondrial deficiency and cardiomyopathy. Role of Reactive Oxygen Species
ROLROS 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.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Mitochondrial diseases are now considered to be among the most common forms of genetic disorders, with a minimum prevalence of 1 in 5000 individuals. They can be caused by mutations in either the nuclear or the mitochondrial DNA (mtDNA). One of the most well characterized clinical presentations is neuromuscular dysfunction, followed by cardiomyopathy, generally in the form of hypertrophic cardiomyopathy. Nowadays there are several clinical treatments approved for mitochondrial diseases. However true treatment is, with some exception, unavailable due to the complexity of the disease and the side effects observed.Several mutations involving mt-tRNA genes (mainly Leu1, Lys and Ile), mt-encoded protein and nuclear encoded protein genes have been associated with cardiomyopathy. Some of these mutations have been deeply studied in a cybrid cell culture model at the biochemistry level. However, very little is known about the signalling pathways that could lead to the development of cardiomyopathy. Mitochondrial physiology and biogenesis are deeply involved in the initiation and progression of the disease, through reactive oxygen species (ROS) production, energy deficiency and decrease in mitochondrial respirasome formation, as initial steps in the formation of the plaques. Recently, it as been demonstrated the role of some mitochondrial biogenesis-related genes, such as PGC1a, in mitochondrial fusion, pointing to the importance of the balance between mitochondrial fusion-fission in the progression of the disease. Interestingly, some of the mutations described in cardiomyopathy are very ROSgenic, strongly pointing to ROS and mitochondrial deficiency as an initial step in the onset of the cardiomyopathy.The aim of this project is to better understand the involvement of mitochondria in cardiomyopathies using different models of mitochondrial diseases that curse with increase ROS production.
Оригинален текст от CORDIS (на английски).
Участници
- CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III (F.S.P.) · MadridКоординаторИспания
Връзки
Данни: CORDIS, © Европейски съюз