B01
Ventricular remodeling under regenerative and pathological conditions
Our research project investigates the role of Interleukin-11 (IL-11) signaling in heart tissue regeneration, particularly focusing on comparing regenerative responses in zebrafish to the fibrotic responses observed in mammals. The key aim of project B01 is to identify and explore signaling pathways that enable zebrafish to repair heart damage without adverse fibrotic remodeling and to translate these findings into therapeutic approaches for heart conditions in humans, especially in cases involving right ventricular (RV) fibrosis caused by conditions such as pulmonary hypertension (PH).
Figure 1: Il11 signaling limits epicardial- and endocardial - derived myofibroblast differentiation after cardiac injury.
Quantitative lineage tracing of endothelial fli1+and epicardial-derived tcf21+ cardiac stromal cells. Interleukin-11 receptor (il11ra) mutants show a significant increase in cells from both lineages expressing the myofibroblast marker smooth muscle actin (SMA) after tissue injury (12). Box centered on endocardial endothlial cells (ECCs). Scale bars=100μm (left) and 10μm (right).
Specific goals:
- Comparative Analysis: We will compare IL-11 signaling pathways in zebrafish and mammals (mice), utilizing advanced techniques such as multiomic analysis. This will allow us to investigate the molecular differences in IL-11-mediated signaling that lead to regenerative versus fibrotic outcomes.
- Pharmacological and Genetic Manipulation: We aims to manipulate IL-11 signaling pathways in mammalian models (mice) using small molecule antagonists and agonists, as well as generating genetically modified mice. The purpose is to shift signaling toward pro-regenerative responses while minimizing fibrosis, specifically focusing on heart and lung tissues.
- Investigation of ACVR2A and ACVR2B Signaling: We are investigating the roles of ACVR2A and ACVR2B signaling in heart regeneration and fibrosis, as we and others have identified these pathways as crucial in regulating the balance between regeneration and fibrosis formation.
- Identification of Candidate Genes: Utilizing zebrafish as a model for high-throughput gene analysis, we will test candidate genes related to fibrosis and regeneration, identified from studies on chronic thromboembolic pulmonary hypertension (CTEPH) patients and animal models.
Ultimately, our research intends to develop new treatments for heart failure and other fibrotic conditions, by promoting regenerative healing while reducing fibrotic scarring in the heart and lungs.