Project Details
Projekt
Mechanisms of aortic valve calcification driven by clonal hematopoiesis mutations (Project A2)
Subject Area
Cardiology, Angiology
Hematology, Oncology
Hematology, Oncology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 515629962
Calcific aortic valve disease is a common condition that can cause valvular stenosis and heart failure, and currently there is no therapy other than valve replacement for this disease. Recent studies have shown that somatic mutations in TET2, which is associated with clonal hematopoiesis (CH), may contribute to the development and progression of various cardiovascular diseases, including aortic valve stenosis (AVS). However, the mechanistic and functional link between CH and AVS remains poorly understood. The goal of this study is to investigate whether somatic mutations in TET2 cause or accelerate AVS. To achieve this goal, the study will employ a multifaceted approach. The study will use single-cell RNA sequencing to analyze immune cells in patients with and without TET2 mutations and AVS. The focus will be on monocyte/macrophage-mediated calcification processes, but other immune cell types will also be examined. Work Package 2 will use a novel sequencing method called MutDetect-Seq to identify cells with TET2 mutations, determining mutant cell-associated altered transcriptomes and ligand-receptor interactions between mutant and non-mutant cells. A natural barcoding approach (MAESTER) will be used to trace the lineages and relative ages of detected clones, providing insights into clonal dynamics. Clinical implications and in-depth insights of CH and interactions with other genetic endpoints will be provided. Specifically, we will address confounding influences of single nucleotide polymorphisms (SNPs) and loss of Y chromosome on clinical outcomes. As CH mutations are known to promote cytokine signaling, it is likely that similar SNPs may alter prognosis and clinical course for AVS patients with CH and the development of AVS. Even further, we will interrogate a novel player in cardiovascular disease, hematopoietic mosaic loss of Y chromosome. Hematopoietic mosaic loss of Y chromosome associates with age with a higher incidence in men than CH mutations. In fact, loss of Y chromosome in patients who successfully underwent transcatheter aortic valve replacement (TAVR) have been shown to have a worse prognosis, and loss of Y chromosome circulating monocytes have distinct profiles associated macrophage-driven fibrosis. Interaction of loss of Y chromosome with CH mutations on prognosis and clinical parameters will also be determined. The results of this study could lead to the development of new therapies that target the specific mechanisms that contribute to the development and progression of AVS in patients with CH mutations. This has the potential to improve outcomes for patients with AVS, who currently have limited treatment options beyond valve replacement. The study aims to provide insights that could lead to the development of new therapies for AVS patients with TET2 mutations, improving their treatment options beyond valve replacement.
DFG Programme
Research Units
