SFB 1550:  Molecular Circuits of Heart Disease

• Subject Area: Medicine
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 464424253

Heart disease is a leading cause of morbidity and mortality worldwide. In particular, heart failure and arrhythmias due to inherited cardiomyopathies and acquired causes put growing strain on health care systems. To advance heart disease therapies, we see an urgent medical need for more individualized and tailored treatments in the future. Recent advances in disease modeling and multi-OMICs technologies now allow us to gain a better view on the full complexity of heart disease involved in both primary etiology and risk for heart disease. The CRC 1550 uses a novel approach that integrates the knowledge of specific causes and pathways as well as disease phenotypes by tightly intertwining experimental and patient data with systems biology and mathematical modelling approaches. By doing so, we aim to unravel the underlying molecular circuitry of heart disease. The CRC 1550 puts forward the hypothesis that each heart disease phenotype is caused by specific molecular circuits that partly overlap with other phenotype circuits. Understanding this overlap will allow us to unmask the key hubs involved in heart disease, thereby paving the way for new safe translational concepts to predict, prevent and treat heart disease. The projects for this collaborative research center were selected to jointly address the following fundamental questions: (i) How do gene mutations result in reprogramming of cardiomyocyte function; (ii) how do stress signals affect cardiomyocyte function and their instructive signaling towards other cell populations within the heart; (iii) how do genes and environmental cues work together to shape cardiomyocyte function and dysfunction; (iv) what are the key shared molecular nodes in inherited and acquired heart disease? We trust that genotype-informed mechanistic research and uncovering the influence of environmental stress will (i) identify mechanisms close to the roots of disease; (ii) decode overlapping molecular circuits and shared disease mechanisms; (iii) reveal the complex interplay between classically separately studied processes and hidden relays; and (iv) unmask cardiomyocyte-born signals that direct the cardiac microenvironment. To maximize synergies, we will focus in the first funding period on cardiomyocyte-intrinsic mechanisms at the layers of gene expression and protein homeostasis. It is our strong conviction that only a detailed understanding of the single components and wires of the molecular circuitry of heart disease will enable conceptual advances and development of innovative translational strategies. Our cross-disciplinary team is highly committed to this joint endeavor and is in a unique position to catalyze important discoveries that in later funding periods will be translated in a step-wise process to eventually improve the care of individual heart patients.

• DFG Programme: Collaborative Research Centres

Current projects

• A01 - Metabo-epigenetic regulatory circuits of heart disease caused by inherited and acquired lipid accumulation (Project Heads Backs, Johannes ;  Schulze, Almut )
• A02 - Function and modulation of genomic cardiomyopathy enhancers (Project Head Gilsbach, Ralf )
• A03 - Interplay between epigenetics and metabolism in cardiac laminopathies (Project Head Dobreva, Gergana )
• A04 - Modelling and decoding the mechanisms of left ventricular non compaction cardiomyopathy (Project Head Furlong, Ph.D., Eileen E. M. )
• A05 - Role of the splice target CAMK2D in RBM20 cardiomyopathy (Project Head van den Hoogenhof, Ph.D., Maarten )
• A06 - Decoding the regulatory network of RBM20 (Project Head Steinmetz, Ph.D., Lars )
• A07 - STAR family function and interaction with RBM20 for intervening alternative splicing (Project Head Meder, Benjamin )
• A08 - Dysregulation of mRNA decay in MYBPC3 hypertrophic cardiomyopathy (Project Heads Seeger, Timon ;  Stoecklin, Georg )
• A09 - Random monoallelic gene expression in inherited cardiomyopathies (Project Head Heard, Ph.D., Edith )
• B01 - Impact of the translation elongation factor 1a on cardiac growth and function (Project Head Heineke, Jörg )
• B02 - The role of unconventional RNA-Binding proteins in the failing heart (Project Heads Hentze, Matthias ;  Völkers, Mirko )
• B03 - Targeting autophagy in cardiac remodeling via FYCO1 (Project Head Frey, Norbert )
• B04 - The role of the AP-1 transcriptional complex during cardiac remodeling (Project Head Beisaw, Arica )
• B06 - Cardiocrine signaling as a regulator of cardiac homeostasis and fibrosis (Project Head Leuschner, Florian )
• B07 - Control of cardiac homeostasis and cardiocrine signaling by protein arginine methyltransferases (Project Heads Backs, Johannes ;  Dieterich, Christoph )
• B08 - Role of ETV transcription factors in atrial cardiomyopathy (Project Head Schmidt, Constanze )
• B09 - Unraveling molecular circuits leading to catecholamine-driven ventricular arrhythmias (Project Heads Freichel, Marc ;  Levinson, Ph.D., Rebecca )
• B10 - Deciphering molecular circuits of cardiac remodeling and dysfunction via an integrative reverse approach (Project Heads Frey, Norbert ;  Saez-Rodriguez, Julio )
• INF - INFrastructure for Biobanking, Data Management and Bioinformatics (Project Heads Dieterich, Christoph ;  Saez-Rodriguez, Julio ;  Weis, Tanja )
• S01 - Integrated Research Training Group for CardioScience (Project Head Freichel, Marc )
• S02 - Disease modeling (Project Heads Dewenter, Matthias ;  Seeger, Timon )
• Z - Central Tasks of the Collaborative Research Center (Project Head Backs, Johannes )

• Applicant Institution: Ruprecht-Karls-Universität Heidelberg
• Participating Institution: Deutsches Krebsforschungszentrum (DKFZ); European Molecular Biology Laboratory (EMBL)
• Spokesperson: Professor Dr. Johannes Backs