Project description
Developmental origin of pulmonary hypertension
Pulmonary hypertension (PH) refers to abnormally elevated pressure in pulmonary blood circulation. Chronic pulmonary hypertension is a lethal disease characterised by the accumulation of cells in the pulmonary vasculature with aberrant expression of genes driving apoptosis resistance, proliferation, inflammation and matrix remodelling. The previous study carried out by the project team obtained evidence for the de novo onset of foetal epigenetic programming in adult PH and the postnatal maintenance of such programming in persistent pulmonary hypertension of the newborn (PPHN). The EU-funded Restoring Roots project will investigate the contribution of a specific set of transcription factors to vascular remodelling in PH and PPHN. The proposal is highly innovative as it explores the developmental origin of PH and PPHN and offers novel therapeutic strategies.
Objective
Chronic pulmonary hypertension (PH) is a lethal disease characterized by the accumulation of persistently activated cell types in the pulmonary vasculature, exhibiting aberrant expression of genes driving apoptosis resistance, proliferation, inflammation and matrix remodeling. Current vasodilatory therapies for PH do not normalize these activated phenotypes. I have performed an “integromics” approach – combining epigenetic and transcriptional analyses to comprehensively elucidate the underlying molecular mechanisms. This approach provided evidence for the recapitulation of a “fetal-like” “remodeled” lung vascular phenotype, orchestrated via central lung developmental transcription factor (TF) networks with particular emphasis on TBX4, TBX5 and SOX9. Moreover, in addition to de-novo onset of this “fetal epigenetic programming” in adult PH, postnatal maintenance of such programming may underlie persistent pulmonary hypertension of the newborn (PPHN). Placing TBX4/TBX5/SOX9 at the center, I will probe this hypothesis i.e. will define their contribution to vascular remodeling processes underlying neonatal and adult PH. Studies will be performed in primary vascular cells and viable tissue slices from human/ experimental PH lungs, and various transgenic mouse lines. Furthermore, I will address the relationship among TBX4/TBX5/SOX9 in a transcription network that controls PH development using CRISPR–dCas9-activator mice. In addition, uncovering the TBX4/TBX5/SOX9-epigenetic circuitry by profiling epigenetic landscape ([sc]RNA-, ChIP-, ATAC-, MeD-, histone PTMs- seq) in both “pathological remodeling” and the loss of “physiological reverse remodeling” in PPHN, I aim to harness novel intervention strategies (locus-specific epigenetic modifications) to reverse aberrant remodeling and foster regeneration of lung vasculature. Hence, this proposal is highly innovative as it explores the hypothesis of a “developmental origin” of PH and PPHN and offers novel therapeutic strategies.
Fields of science
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
35390 Giessen
Germany