Project Details
Projekt
Epigenetic-metabolic contribution to inflammatory phenotypes of CH in pulmonary hypertension (Project A3)
Applicant
Professorin Dr. Soni Savai Pullamsetti
Subject Area
Cardiology, Angiology
Hematology, Oncology
Hematology, Oncology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 515629962
Pulmonary hypertension (PH) is a progressive and life-threatening cardiopulmonary disease characterized by remodeling of the pulmonary vascular wall and elevated mean pulmonary arterial pressure leading to right heart hypertrophy and failure. Recent studies suggest that patients with PH harbor the increased burden of DNMT3A and TET2 somatic and germline deleterious mutations, which suggest a potential association between clonal hematopoiesis of indeterminate potential (CHIP) and PH. The putative hub feature of all aged-associated CHIP pathologies is the pro-inflammatory state of immune cells. However, the underlying molecular mechanism of this pro-inflammatory phenotype is not known precisely. Recent studies by our group revealed a significant contribution of CHIP mutations with predominant DNMT3A mutations to the proinflammatory phenotype in COPD and associated PH patients (group 3 PH), suggesting a strong association and causative role of CHIP at PH. DNA methylation genome sequencing of CHIP patients revealed massive DNA hypomethylation in DNMT3A CHIP patients. Our further analysis indicated that inflammatory-associated genes/locus methylation status are not affected by DNMT3A CHIP but mainly metabolic-associated genes/loci are hypomethylated under DNMT3A CHIP which regulate the tricarboxylic acid (TCA) cycle and fatty acid metabolic pathways. Moreover, metabolomic analysis of DNMT3A CHIP plasma showed enrichment of TCA cycle metabolites, suggesting functional effects of hypomethylation of metabolism-associated genes/loci. Furthermore, we demonstrated that modulation of TCA cycle enzymes attenuated the pro-inflammatory phenotype and ex vivo cultured monocyte/macrophage lines carrying DNMT3A CHIP mutations. Moreover, our studies show that hematopoietic stem cell (HSC) differentiation is significantly impaired in the absence of the TCA cycle intermediate itaconate, suggesting a role in HSC dominance in CHIP DNMT3A and TET2 mutants. In this project we aim to investigate the impact of CHIP mutations on metabolism and its potential role in the development or progression of PH. As a result, we expect to gain a deeper understanding of metabolic dysregulation in CHIP-associated PH pathogenesis and identify new therapeutic strategies that might improve patient outcomes with CHIP-associated PH. Focusing specifically on DNMT3A and TET2 CHIP mutations and employing various in vitro, ex vivo and in vivo models of PH, we would like to address the following aims: 1) Characterize the epigenetic-metabolic axis in PH patients with DNMT3A and TET2 CHIP mutations by focusing on the monocyte/macrophage cell line as the major immune cells involved in the inflammatory phenotype of CHIP patients, 2) Metabolic contribution to CHIP clonal dominance, 3) Assess the role of DNMT3A and TET2 CHIP-driver mutations in PH pathogenesis by focusing on the epigenetic-metabolic axis, and 4) Therapy with metabolic modulators in DNMT3A mut-PH and Tet2 mut-PH mouse models.
DFG Programme
Research Units
