CRC1002: Modulatory Units in Heart Failure

https://sfb1002.med.uni-goettingen.de/ (Research Data Platform)
https://gepris.dfg.de/gepris/projekt/193793266?language=en (DFG Gepris entry)
With a prevalence of between two and four percent, heart failure remains one of the most common diseases in Europe. Although tremendous progress has been made in its treatment, the morbidity and mortality of affected patients remains high. Advanced heart failure can still only be treated palliatively.We define modulatory units as cell-based and/or genetic principles that organize and control important cardiac functions, which are subject to disruption and cause cardiac dysfunction in heart failure models and humans, and therefore represent treatment targets. For example, during the second funding period, CRC 1002 contributed to the characterization and identification of molecular mechanisms that affect microdomain structures of excitation-contraction coupling processes and associated organelles, including mitochondria. We have continued to develop advanced imaging techniques for cells, tissues and organs, as well as in vivo analyses up to the in-depth characterization of patient cohorts. CRC 1002 provides an important platform for analyzing the molecular mechanisms of intracellular calcium and sodium signaling in human tissue samples as well as human stem cell and animal models. In addition, gene editing protocols were developed for cutting-edge mechanistic interrogation of human iPSC-derived cardiomyocyte and fibroblast models, as well as for studies using engineered heart muscle. A central goal of CRC 1002 is to identify new treatment targets in heart failure and to develop therapeutic strategies. The first and second funding periods have uncovered such novel targets, of which some are already at a clinical trial level. For example, we identified methylation of the RASAL1 gene as a key pathogenetic mechanism in myocardial fibrosis and from this developed a new therapeutic antifibrotic strategy. During the third funding period mechanisms underlying the transition from compensated hypertrophy to cardiac failure, in particular myocardial fibrosis, impaired calcium cycling, and altered energy metabolism will be evaluated. The unique resources available in the human biobank will provide a deeper insight into the mechanisms of myocardial reverse remodeling and clinical improvement after relief of pressure overload following aortic valve implantation performed to treat pressure overload-induced heart failure. Moreover, based on findings from the previous funding periods, we will study a new antifibrotic treatment in patients with aortic stenosis and a high degree of myocardial fibrosis.In summary, CRC 1002 will continue to improve the in-depth and mechanistic understanding of the pathophysiology of heart failure. Most importantly, we will continue to strive to close conceptual gaps and to improve treatment of heart failure patients with new therapeutic options. By monitoring the outcome of selected interventions and a thorough characterization of patient data and biosamples prior to these interventions, our studies have the potential to provide new perspectives towards a more effective, individualized treatment of heart failure.