Descrizione del progetto
Allo studio il ruolo delle cellule epiteliali postnatali nella salute umana dopo l’esposizione precoce a patogeni
Il microbiota enterico, il sistema immunitario mucosale e la barriera epiteliale sono i fattori che determinano l’omeostasi intestinale ospite-microbi dopo la nascita. Il sistema immunitario mucosale e la formazione del microbiota enterico sono stati ampiamente studiati al contrario del coinvolgimento postnatale delle cellule epiteliali. Il progetto EarlyLife, finanziato dall’UE, si propone di creare una mappa esaustiva della differenziazione del tipo di cellule epiteliali postnatali e di approfondire l’impatto di infezioni nei primi anni di vita da parte di gravi patogeni umani batterici, virali e parassitari su malattie metaboliche, infiammatorie e immuno-mediate a lungo termine. Tali effetti a lungo termine saranno studiati dal punto di vista funzionale usando la profilazione epigenetica e trascrittomica, esperimenti di trasferimento del microbiota e colture di organoidi di cellule staminali umane insieme a modelli genetici in vivo.
Obiettivo
Infections of the gastrointestinal tract and their long-term consequences remain a major cause of childhood mortality and morbidity worldwide. In addition, early life is recognized as a critical and non-redundant time period to prime the mucosal tissue and establish the enteric microbiota that determine the risk to develop prevalent inflammatory, immune-mediated, and metabolic diseases. Three factors: the enteric microbiota, the mucosal immune system and the epithelial barrier cooperate to establish intestinal host-microbial homeostasis after birth. Maturation of the mucosal immune system and establishment of the enteric microbiota have been extensively studied. In contrast, postnatal evolvement of epithelial cell type heterogeneity and functional specialization and the influence of enteric infection on this process have not been explored. With EarlyLife, I propose to further advance innovative, multiscale technical approaches and analytical protocols in combination with novel in vivo models to generate the first comprehensive map of postnatal epithelial cell type and subtype differentiation and analyze the impact of early life infection by important human bacterial, viral and parasitic pathogens. Long-term inflammatory, immune-mediated and metabolic effects will be functionally studied using epigenetic profiling, microbiota-transfer experiments, stem cell organoid culture and co-culture, as well as genetic models. Identified mechanisms will be confirmed using single-cell analysis of human mucosal biopsies, human stem cell organoids and transcriptomic profiling of human fecal samples. As a result, I expect to identify mechanisms of enhanced infection susceptibility of the neonate, decipher the critical and non-redundant influence of the postnatal period for mucosal homeostasis and explain the role of early life imprinting for long-term immune-mediated, inflammatory and metabolic diseases.
Campo scientifico
- social sciencessociologydemographymortality
- medical and health sciencesbasic medicineimmunology
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- medical and health sciencesclinical medicineobstetricspostnatal care
- medical and health sciencesbasic medicinephysiologyhomeostasis
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-ADG - Advanced GrantIstituzione ospitante
52074 Aachen
Germania