Project Details
Projekt
The role of clonal hematopoiesis driven by DNMT3A mutations in regulating innate immune cell functions in the context of myocardial infarction
Subject Area
Cardiology, Angiology
Toxicology, Laboratory Medicine
Toxicology, Laboratory Medicine
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 555094884
Myocardial infarction (MI) initiates a dynamic inflammatory response, largely coordinated by cells of innate immunity, that plays a key role in determining the extent of cardiac injury, as well as of subsequent repair, and long-term cardiac function. Cardiomyocyte death triggers an initial inflammatory response that drives accumulation of neutrophils as well as monocyte-derived macrophages. In later phases of MI, macrophages with a restorative phenotype emerge, which contribute to remodelling and repair. A disruption of such reparative functions can lead to adverse remodeling and heart failure. Several recent studies have highlighted the versatility of cardiac macrophage subsets and their multiple roles during the inflammation and repair phases of MI. Furthermore, clonal hematopoiesis of indeterminate potential (CHIP), driven by somatic mutations in hematopoietic stem and progenitor cells, particularly in epigenetic regulators, such as DNA methyltransferase 3A (DNMT3A), has emerged as a factor that enhances the risk for cardiovascular disease and MI. DNMT3A-mutant myeloid cells display elevated inflammatory responses and have been linked to worse outcomes after MI. Our group has expertise in innate immunity, the process of inflammation and its resolution and more recently in the field of clonal hematopoiesis. In the present project, we hypothesize that DNMT3A-associated clonal hematopoiesis may aggravate MI-related myocardial damage via (a) exacerbating the inflammatory phase of MI and (b) impairing post-MI cardiac repair. Additionally, we aim to explore how clonal hematopoiesis driven by DNMT3A mutation can interact with obesity / metabolic syndrome to potentially exacerbate MI-related injury. This project will thus focus on how DNMT3A-driven clonal hematopoiesis alters myeloid cell function during the course of MI, thereby potentially impairing cardiac repair.
DFG Programme
Research Units
