Vacchi-Suzzi, Caterina. MicroRNAs regulatory networks in cardiotoxicity. 2012, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_9942
In 1993 Victor Ambros, Rosalind Lee and Rhonda Feinbaum (Lee et al., 1993) described for the first time in C. elegans the role of short non-coding RNAs, called microRNAs. MicroRNAs pair with target mRNAs via sequence complementarity, and lead to mRNA degradation or translation inhibition (Filipowicz et al., 2008; Guo et al., 2010). MicroRNAs are implicated in many biological processes and in the evolution of the complexity of superior organisms, for review see (Bartel, 2004; Berezikov, 2011). Their role in cardiovascular development and diseases has been supported by an increasing number of publications, for review see (Kinet et al., 2012; Small and Olson, 2011). Recently, tissue-specific microRNAs were found in a variety of body fluids following drug-induced tissue injury (Wang et al., 2009). In particular, myocardial necrosis of different etiologies (such as acute coronary syndrome and myocardial infarction) caused an increase of heart enriched microRNAs in plasma/serum of patients, as reviewed by (McManus and Ambros, 2011).
This work is aimed at increasing our knowledge about cardiac microRNAs function in different toxicological contexts and across species.
Chapter 1 will give an overview of drug safety assessment focusing on the cardiovascular system, microRNAs biology and their potential as toxicity biomarkers.
In Chapter 2 I will illustrate an example of drug-induced cardiac injury, and its impact on expression of microRNAs in rats’ hearts. Chronic treatment of rats with low amounts of doxorubicin (an anti-tumoral compound) caused myocardial vacuolation in ventricular tissue and a significant increase of specific microRNAs and genomic indicators of cardiomyopathy. We found that Sipa1 could be directly inhibited by miR-34c by using a luciferase assay. Notably, the phenotypic anchoring of microRNAs with histopathological read-outs in the tissue showed that over-expression of miR-216b in the heart preceded the rise of overt lesions.
Chapter 3 will describe an approach to determine the distribution of mRNAs and microRNAs in different cardiac structures in rat, dog and Cynomolgus monkey. We showed that microRNAs could discriminate the different heart structures as good as mRNAs. We also assessed the expected anti-correlation between microRNAs levels and their predicted target mRNAs, and showed that mRNAs of 4 genes implicated in cardiac diseases and muscular development could be inhibited at the post-transcriptional level by 4 distinct microRNAs. We propose that our mRNAs and microRNAs data sets could be used to assess the human relevance of preclinical findings in these 3 species, and to derive potential tissue and circulating biomarkers for drug-induced cardiac injury.
In conclusion, profiling microRNAs have the potential to help biomedical research in bringing drugs to patients, since they can shed light on toxicity mechanisms in the tissues (Taylor and Gant, 2008) and are a source of translatable non-invasive toxicity biomarkers in body fluids.
|Committee Members:||Couttet, Philippe and Filipowicz, Witold|
|Faculties and Departments:||05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||180 Bl.|
|Last Modified:||30 Jun 2016 10:49|
|Deposited On:||23 Jul 2012 13:45|
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