Molecular Genomics Intracellular Calcium-Handling in Diastolic Dysfunction, Heart Failure and Arrhythmias

Coordinator:    Dr. Stephan Lehnart
Institution: Georg-August-Universität Göttingen
Subproject 8 investigates gene variants of physiologically relevant calcium (Ca2+) modulatory proteins as a cause of depressed cardiac pump function (diastolic dysfunction or heart failure) and of rhythm disorders  (arrhythmias). Gene variants are identified in patient cohorts together with subproject 1 through Genome Wide Association Studies (GWAS) and are confirmed through additional investigations. Our ongoing work included GWAS- and replication studies for the originally postulated gene variants of the physiologically relevant Ca2+ regulatory NCX1 und RyR2 genes, which could not be replicated so far (see also report of subproject 1).

Genome-wide, disease mechanism oriented studies investigated heart cells affected by patient mutations of the cardiac Ca2+ release channel RyR2 (ryanodine receptor). For the first time a molecular role of RyR2 as stress sensory mechanism was shown, which modulates intracellular Ca2+ release and contractile function of the heart. On the other hand, disease mechanisms during pathologically sustained stress and RyR2 patient mutations were investigated, which lead to abnormally increased intracellular Ca2+ release, life-threatening arrhythmias, and potentially additional changes. Genome-wide expression analysis identified multifactorial changes of several signaling pathways in hearts of transgenic animals with RyR2 patient mutations. Already few days of exposition to sustained stress caused significant expression changes of physiologically important protein networks and pronounced cardiac dysfunction. In summary, stress-dependent molecular mechanisms were identified, which may explain a common form of cardiac dysfunction in heart failure (diastolic dysfunction) for the first time through specific defects caused by mutant RyR2 channels.

To address the disease causative onset of cardiac dysfunction, elaborate genome-wide analysis during different time points of sustained stress are investigated. In this context, a new class of RyR2-stabilizing compounds is tested in transgenic mouse models with RyR2 patient mutations to develop novel therapeutic strategies against the onset and progression of the observed cardiac dysfunction mechanisms. Thereby, ongoing investigations may identify additional, as yet unknown target proteins, molecular signatures for diagnostic staging, and novel therapeutic interventions.
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