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Gut epithelial dynamics and function at the nexus of early life infection and long-term health

Descripción del proyecto

Estudio de la función de las células epiteliales posnatales en la salud humana tras una exposición temprana a patógenos

La microbiota entérica, el sistema inmunitario de las mucosas y la barrera epitelial son los factores que determinan a homeostasis huésped-microbio tras el nacimiento. El sistema inmunitario de las mucosas y la formación de la microbiota entérica han sido ampliamente estudiados, pero no así la evolución posnatal de las células epiteliales. El proyecto EarlyLife, financiado con fondos europeos, se propone crear un mapa exhaustivo de diferenciación entre tipos de células epiteliales posnatales e investigar el impacto de la infección en las primeras fases de la vida por patógenos parasitarios, víricos y bacterianos humanos sobre las enfermedades metabólicas, inflamatorias e inmunitarias a largo plazo. Estos efectos a largo plazo se estudiarán desde un punto de vista funcional mediante la creación de perfiles transcriptómicos y epigenéticos, experimentos de transferencia de microbiota y cultivos de organoides de células madre humanas, en combinación con modelos genéticos «in vivo».

Objetivo

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.

Régimen de financiación

ERC-ADG - Advanced Grant
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Coordinador

UNIVERSITAETSKLINIKUM AACHEN
Aportación neta de la UEn
€ 2 450 000,00
Dirección
Pauwelsstrasse 30
52074 Aachen
Alemania

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Región
Nordrhein-Westfalen Köln Städteregion Aachen
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Otras fuentes de financiación
€ 0,00

Beneficiarios (1)