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Neuron-associated macrophages in the gut as novel target for the treatment of enteric neuropathies

Descripción del proyecto

Un sistema nervioso entérico sano depende de los macrófagos residentes

El tubo gastrointestinal cuenta con su propio sistema nervioso entérico (SNE). La neuropatía entérica (NE), la disfunción de las neuronas de la pared intestinal, tiene como resultado la estasis del contenido luminal, la cual se manifiesta en forma de malabsorción, dolor crónico, vómitos, meteorismo y estreñimiento grave. El proyecto financiado con fondos europeos NEUMACS está evaluando la provocativa hipótesis de que la alteración del apoyo al SNE de una subpoblación específica de macrófagos asociados a neuronas (NA-MF, por siglas en inglés) produce neuropatía entérica, lo cual da lugar a trastornos neuronales y apoptosis. Mediante el uso de métodos innovadores, el proyecto caracterizará las poblaciones de NA-MF e investigará los mecanismos que causan su incapacidad para apoyar y proteger el SNE. La información obtenida en el marco del proyecto permitirá identificar nuevas dianas terapéuticas para el tratamiento de la neuropatía entérica.

Objetivo

The gastrointestinal tract has the vital task to digest and absorb ingested food, a complex process requiring coordinated integration of motility, secretion, vascularization and absorption. Thereto the gastrointestinal tract is equipped with its own nervous system, the enteric nervous system (ENS), capable of controlling gut function independently of input from brain or spinal cord. Reduction in number or dysfunction of the neurons within the gut wall, also referred to as enteric neuropathy, significantly impacts on gut function, resulting in stasis of luminal contents and malabsorption, chronic pain, vomiting, bloating and severe constipation. Enteric neuropathies are common in prevalent disorders such as obesity, diabetes, and ageing, all major contributors to the health burden. Despite the continuous global increase in incidence of these disorders, the insight in the mechanisms leading to the reduction or dysfunction of enteric neurons is limited and most importantly, adequate treatment is lacking. Recently, we collected evidence that survival of enteric neurons is guaranteed by a unique subpopulation of resident macrophages closely associated to the ENS and expressing a typical neuroprotective / -supportive transcriptome. In line, depletion of these neuron-associated macrophages (NA-MF) results in apoptosis and a reduction in number of enteric neurons leading to severely impaired gastrointestinal motility. We pose the provocative hypothesis that enteric neuropathy results from impaired support to the ENS by NA-MF, leading to neural distress and apoptosis. Using state-of-the-art methods, we will first characterize in depth the NA-MF population to subsequently unravel the mechanisms leading to failure of NA-MF to support and protect the ENS in animal models and in patients. These ground-breaking insights will allow us to identify therapeutic targets for the treatment of enteric neuropathies, representing an exponentially growing health problem of the 21st century.

Régimen de financiación

ERC-ADG - Advanced Grant

Coordinador

KATHOLIEKE UNIVERSITEIT LEUVEN
Aportación neta de la UEn
€ 2 500 000,00
Dirección
Oude markt 13
3000 Leuven
Bélgica

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Región
Vlaams Gewest Prov. Vlaams-Brabant Arr. Leuven
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Otras fuentes de financiación
€ 0,00

Beneficiarios (1)