Inflammostrome
Financiado
Stromal cells as primary drivers of immunopathology towards targeted disease mo...
Stromal cells as primary drivers of immunopathology towards targeted disease modification in spondyloarthritis
Pro-inflammatory cytokines play a crucial role in chronic inflammatory diseases. Focusing on spondyloarthritis (SpA), a prevalent and debilitating rheumatic condition characterized by inflammation and abnormal new bone formation,...
Pro-inflammatory cytokines play a crucial role in chronic inflammatory diseases. Focusing on spondyloarthritis (SpA), a prevalent and debilitating rheumatic condition characterized by inflammation and abnormal new bone formation, we demonstrated that TNF and IL-23/IL-17 inhibition potently blocks inflammation. However, these treatments have no proven effect on pathologic new bone formation and the resulting structural damage, indicating the unmet need for understanding upstream disease mechanisms. Immune cells, in particular myeloid cells, have been shown to be the major sources of TNF and IL-23 in experimental models. However, we and others failed to demonstrate abnormal cytokine production by myeloid cells in human SpA. What drives these pathogenic cytokines thus remains unknown.
We recently found that SpA synovial tissues contain an abnormal stromal population of myofibroblasts, that these myofibroblasts express TNF and IL-23 in vivo and in vitro when exposed to cellular stress, and that stromal expression of these cytokines does not only drive inflammatory responses in vitro but is required and sufficient to induce experimental SpA in vivo. Therefore, we propose that stressed stromal cells can act as primary drivers of cytokine-mediated tissue inflammation and remodelling. Using a translational approach - dynamic sampling of primary human target tissues, functional experiments ex vivo and in vitro, animal models, and targeted interventions in patients – we aim to unravel the role of stromal cells in SpA by defining: 1) the molecular profile of the stromal alterations, 2) the mechanisms of cytokine production by stromal cells, 3) the activation of downstream inflammatory pathways, 4) the role of stromal alterations in tissue remodeling, and 5) the contribution of stromal pathways to experimental and human SpA. Collectively, this project will allow to validate stromal cells as novel therapeutic targets for SpA and related disorders.
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Duración del proyecto: 42 meses
Fecha Inicio: 2015-06-02
Fecha Fin: 2018-12-31
Fecha Fin: 2018-12-31
Línea de financiación: concedida
El organismo H2020 notifico la concesión del proyecto el día 2018-12-31
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-CoG-2014:
ERC Consolidator Grant
Cerrada
hace 10 años
Presupuesto
El presupuesto total del proyecto asciende a
2M€
Líder del proyecto
Academisch Medisch Centrum AMC
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5
460.69K€ |
Participante