Restoring Roots
Financiado
Pulmonary hypertension aberrant mimicry of lung vascular morphogenesis?
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, pro...
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.
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Duración del proyecto: 63 meses
Fecha Inicio: 2020-06-04
Fecha Fin: 2025-09-30
Fecha Fin: 2025-09-30
Línea de financiación: concedida
El organismo H2020 notifico la concesión del proyecto el día 2020-06-04
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2019-COG:
ERC Consolidator Grant
Cerrada
hace 5 años
Presupuesto
El presupuesto total del proyecto asciende a
2M€
Líder del proyecto
JUSTUSLIEBIGUNIVERSITAET GIESSEN
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5
446.28K€ |
Participante