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Propionic acidemia: impact on the epigenome and the proteome in relation to the cardiac and neurological phenotype

20th national competition for scientific and technical research

Rare diseases

Senior Researcher : Eva María Richard Rodríguez

Research Centre or Institution : Centro de Biología Molecular Severo Ochoa. CSIC - UAM

Abstract

Previous work from our group demonstrates the presence of tissue-specific oxidative stress, mitochondrial dysfunction and altered miRNA signatures in the mouse model of propionic acidemia (PA), one of the most frequent organic acidemias classified as a rare neurometabolic disease. In addition, two induced pluripotent stem cell (iPSC) lines from PA patients-derived fibroblasts and an isogenic control have been generated to be used for cardiomyocytes and neurons differentiation providing new disease cellular models. Propionyl CoA, which accumulates in PA, is a known substrate for histone propionylation, a mark of active chromatin. In this project, we aim to study the specific pathomechanisms contributing to the progression of cardiomyopathy and neurological alterations in PA, underlying major causes of mortality and morbidity of the disease, using PA animal and cellular models.   

Our work will be focused on the study of the impact of PA on the epigenome and proteome, and on the characterization of altered cellular signaling pathways. For that purpose we will carry out the: i) analysis of histone propionylation and its effect on the transcriptome and the interplay with tissue-specific miRNAs; ii) analysis of oxidative PTMs and bioenergetic protein signature; and iii) study of mitochondrial ultrastructure and function, and electrophysiology. The proposed project attains a deeper knowledge of affected cellular pathways and molecular mechanisms of PA disease contributing to the pathophysiology and represents moving a step forward in the identification of therapeutic targets in this devastating neurometabolic disease.

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