Projektbeschreibung
Physiologische Rolle des postnatalen Darmepithels bei Erstkontakt mit Krankheitserregern
Darmmikroben, Schleimhautimmunsystem und Epithelbarriere sind die Faktoren, die nach der Geburt für das Ausbilden einer ausgewogenen Darmflora sorgen. Schleimhautimmunsystem und Ausbildung der Darmflora sind bereits gut erforscht, nicht jedoch die postnatale Entstehung von Epithelzellen. Das EU-finanzierte Projekt EarlyLife erstellt eine umfassende Karte der postnatalen Differenzierung von Epithelzelltypen und untersucht, inwieweit sich der Erstkontakt mit bedeutsamen bakteriellen, viralen und parasitären Krankheitserregern auf die Entstehung von Immun-, Entzündungs- und Stoffwechselerkrankungen im späteren Leben auswirkt. Um diese Langzeiteffekte funktionell zu untersuchen, werden epigenetische und transkriptomische Profile erstellt sowie Versuche mit fäkalem Mikrobiomtransfer und Organoidkulturen aus humanen Stammzellen sowie In-vivo-Genmodellen durchgeführt.
Ziel
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.
Wissenschaftliches Gebiet
- 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
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-ADG - Advanced GrantGastgebende Einrichtung
52074 Aachen
Deutschland