Systems biology analysis of cardiac regeneration to improve healing after myocardial infarction

Acute myocardial infarction (MI) represents the major cause for death worldwide. MI results from an athrothrombotic occlusion of coronary vessels leading to insufficient blood supply of the affected heart muscle area. The resulting irreversible myocardial necrosis and replacement fibrosis in the infarct zone and the maladaptive remodeling processes of the entire heart dramatically increase the risk for the development of post-ischemic heart failure and premature sudden cardiac death. Major advances in MI therapy notably increased to survival after MI. However, this success in treatment of acute symptome increased long-term mortality and hospitalization rates due to post-ischemic heart failure. Novel therapeutic approaches to improve healing post-infarct would have enormous social and economic impact.

Myocardial necrosis after cryoapplication in zebrafish. a, atrium; ot, outflow tract; v, ventricle.

In contrast to humans the adult zebrafish exhibits the extraordinary ability to very efficiently regenerate its damaged heart to its original form and function without leaving any traces of scar behind. By cryoapplication to induce myocardial necrosis we can produce very similar conditions as seen in human hearts post-infarct, including cell death, scarring and cardiac dysfunction.

Light microscopic and histologic image as proof of the scar's regeneration process after myocardial necrosis in zebrafish. a, atrium; ot, outflow tract; v, ventricle; dpi, days post infection.

Subsequently however, the zebrafish begins to resorb the scar tissue and initiates cell division to replenish lost heart muscle to reconstitute heart form and function. Hence, adult zebrafish offer the opportunity to study acute processes post-injury as well as to evaluate the cellular and molecular basis for heart regeneration. Regeneration itself describes a highly dynamic process, relying on an orchestrated sequence of various cellular and molecular events.

Consortium organigram

The goal of DeCaRe is to utilize systems biology that integrates chronologically and cell type specific accumulated datasets to capture the dynamics and the complexity of involved processes. Comparative analyses of regenerating zebrafish hearts with samples from non-regenerating mouse and pig hearts post-infarct will be conducted to identify mechanistic overlaps and novel insights that can lead to improved healing after myocardial infarction in humans.

Subprojects in DeCaRe:

SP 1   Identification and characterization of novel miRNA-controlled signalling circuitries during zebrafish heart regeneration 

SP 2   The role of inflammation in cardiac regeneration in Zebrafish

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