Post-transcriptional regulation of autophagy: MiR-216a as a cell...


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Title Post-transcriptional regulation of autophagy: MiR-216a as a cell death-regulating microRNA during myocardial repair
Period 04 / 2012 - unknown
Status Current
Research number OND1348202
Data Supplier NWO


Because microRNAs have recently been involved in cardiac disease, we analyzed microRNA (miRNA) expression profiles of failing human ischemic hearts and uncovered several differentially expressed miRNAs, with miRNA-216a (miR-216a) being strongly increased in expression. Interestingly, predictive algorithms identified many cell-death-related genes as potential direct target genes of miR-216a, one of them being Beclin-1 (Becn1), an autophagy-regulating gene. Because cardiomyocyte demise due to apoptosis and autophagy is a major cellular event in heart failure, this proposal focuses not only on miR-216a and its role in cell death during myocardial repair, but also on identifying other miRNAs that are involved in regulating autophagy in cardiomyocytes. We hypothesize 1) that post-transcriptional mechanisms regulate cell viability by autophagy and 2) that changes in miR-216a expression directly influences cardiac autophagy and remodeling The key objectives are: 1) Identify genes that are directly regulated by miR-216a and 2) define the role of miR-216a regulating cell death in ischemic heart disease; 3) Establish the therapeutic value of miR-216 silencing in cardiac disease and 4) identify other autophagy-regulating miRNAs by high-throughput screening. For objective 1, we will take a bioinformatics approach by combining large-scale proteomics and microarray analyses on genetic and pharmacological models of miR-216a silencing. In objective 2 we will modulate miR-216a expression in vitro and in vivo and expect miR-216a expression levels to directly reflect the degree of cardiac remodeling, by directly affecting autophagy. For objective 3, we will use a pharmacological approach to silence miR-216a in the setting of ischemic heart disease and anticipate subsequent attenuation of post-MI remodeling, revealing a new potential therapeutic strategy in human cardiac disease. For objective 4, we will establish a high content screening (HCS) assay to identify all miRNAs that functionally regulate autophagy in cardiomyocytes in response to cell stresses inducing/inhibiting autophagy and pathological cardiac remodeling.

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Project leader Dr. P.A. da Costa Martins

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