Project Details
Projekt
Interaction of clonal hematopoiesis-driver mutations with heart failure (Project A1)
Subject Area
Cardiology, Angiology
Hematology, Oncology
Hematology, Oncology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 515629962
Clonal hematopoiesis of indeterminate potential, or CHIP, is a common age-related condition, in which acquired mutations in hematopoietic stem cells lead to the expansion of a genetically distinct subpopulation of blood cells. The incidence of clonal hematopoiesis increases with age and was previously shown to associate with a variety of cardiovascular diseases, including heart failure. Mutations in the epigenetic modifier DNA methyltransferase 3A (DNMT3A) are the most common CHIP-driver mutations and are associated with a poor prognosis of patients with heart failure. Gene editing of DNMT3A in hematopoietic stem cells was shown to aggravate heart failure in mice. However, CHIP is defined as the presence of a mutation with a variant allele frequency of at least 2% resulting in at least 4% of circulating myeloid cells harboring the mutation. Therefore, it remains a matter of discussion, how such a minor fraction of circulating blood cells may activate inflammatory and pro-fibrotic processes in cardiac tissue leading to subsequent promotion of diffuse cardiac fibrosis and affecting prognosis in patients harboring these mutations. We hypothesized that the interaction between circulating mutant cells, which are continuously recruited to the heart, with cardiac fibroblasts and endothelial cells may play a prominent role to aggravate diffuse cardiac fibrosis and endothelial dysfunction, thereby promoting disease progression and increased mortality in patients with established heart failure. This project aims at disclosing the mechanisms underlying the interaction of clonal hematopoiesis with heart failure. In three work packages, we 1) will address the molecular mechanisms that drive cardiac fibrosis and remodeling, 2) will disclose a potential dose-response relationship of clonal hematopoiesis and cardiac pathologies, and 3) will use patient cohorts to validate the experimentally gained new insights specifically by assessing inherited genetic variants by single nucleotide polymorphisms (SNPs) to interfere with inflammatory, pro-fibrotic and newly identified pathways. We will first focus on CHIP driver mutations in DNMT3A. In the future, the strategy of the present application may also be applied to other clonal hematopoiesis driver mutations that prove to be important for the control of heart failure in our clinical studies.
DFG Programme
Research Units
