Descrizione del progetto
Origine evolutiva dell’ipertensione polmonare
Con ipertensione polmonare (IP) si intende una pressione anormalmente bassa della circolazione sanguigna polmonare. L’ipertensione polmonare cronica è una malattia letale caratterizzata dall’accumulo di cellule nella vascolarizzazione dei polmoni con un’espressione aberrante di geni che causano resistenza all’apoptosi, proliferazione, infiammazione e rimodellamento della matrice. Lo studio precedente svolto dal team del progetto ha ottenuto prove dell’insorgenza ex novo della programmazione epigenetica fetale nei casi di IP nell’adulto, nonché della conservazione post natale di tale programmazione nei casi di ipertensione polmonare persistente del neonato (IPPN). Il progetto Restoring Roots, finanziato dall’UE, studierà il contributo apportato da un determinato gruppo di fattori di trascrizione al rimodellamento vascolare nell’IP e nell’IPPN. La proposta del progetto è estremamente innovativa poiché esplora le origini evolutive dell’IP e dell’IPPN e offre nuove strategie terapeutiche.
Obiettivo
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.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
35390 Giessen
Germania