Molecular regulation of heart failure
Cardiovascular Biology and Cardiovascular Diseases
Centro Nacional de Investigaciones Cardiovasculares "Carlos III" (CNIC)
DESCRIPTION OF THE OFFER
Our lab studies the molecular mechanisms that regulate cardiac development and heart disease. One of our main interests is the role of alternative splicing (AS) in these processes.
AS is the molecular process that removes introns from immature pre-mRNAs and links exons together in different combinations. This mechanism affects 86% of all human genes and is in part responsible for the great diversity of proteins that are generated from the relatively small number of genes found in the human genome.
Together with the Genomics Unit at the CNIC, we are using high density exon microarrays and deep sequencing to create a global map of AS isoforms expressed during heart failure. We are also studying cis-regulatory sequences and transregulatory splicing factors associated with AS and analyzing their role in the heart by using knockdown and knockout strategies.
A good example of how alternative splicing can dramatically change protein function is the calcineurin variant CnAb1. Calcineurin regulates a wide variety of physiological and pathological processes, including cardiac development and hypertrophy. CnAb1 is a naturally occurring splice variant of the calcineurin A gene which contains a unique C-terminal region, different from the autoinhibitory domain present in other CnA isoforms. We recently showed that CnAb1 regulates cell proliferation and enhances skeletal muscle regeneration. Our results further suggest that CnAb1 protects the heart from the effects of myocardial infarction by improving cardiac function and reducing inflammation and scar formation.