Description du projet
L’inflammation intestinale et l’origine de la maladie de Parkinson
Un nombre croissant de preuves tend à indiquer que la maladie de Parkinson (MP) touche l’intestin avant d’affecter le cerveau, ce qui conduit à l’hypothèse fascinante que l’intestin pourrait être le site de déclenchement de cette pathologie. La théorie selon laquelle la MP trouve son origine dans une agression inflammatoire au niveau de l’intestin est étayée par l’observation suivante: les caractéristiques génétiques liées à la MP modulent également les réponses immunitaires aux agents pathogènes entériques et impliquent un risque d’inflammation intestinale. En s’appuyant sur des organoïdes dérivés de cellules souches de patients, sur des organes sur puce et sur des technologies de séquençage de cellules uniques, le projet PD-GUT, financé par l’UE, entend décoder le rôle de l’inflammation intestinale dans la MP et identifier les médiateurs des contributions des cellules immunitaires à la neurodégénérescence.
Objectif
Burgeoning evidence shows that Parkinson's disease (PD) involves the gut before affecting the brain, leading to the fascinating hypothesis that the gut might be the site of disease initiation. Remarkably, the gut origin of PD is still poorly understood. Multiple triggers could serve as a first insult: infections, dysbiosis, and inflammatory bowel diseases (IBDs). All these conditions ultimately converge on intestinal inflammation. Thus, an intriguing hypothesis is that PD is a systemic illness that originates from an inflammatory insult in the gut. This hypothesis is based on the observation that genetic traits relevant for both sporadic and familial PD also modulate immune responses to enteric pathogens and confer risk to IBDs. To dissect shared mechanisms among these seemingly unrelated diseases, I envision a multi- and interdisciplinary project with a unique integration of competences in neuroscience, immunology, and microbiology. Moving beyond the state of the art, I will combine patient stem cell-derived organoid, organ-on-a-chip, and single-cell sequencing approaches to decode the role of intestinal inflammation in PD and to identify new mediators of immune cell contributions to neurodegeneration. Specifically, I will i) mechanistically dissect cell type-specific host immune responses to intestinal pathogens and their link to PD; ii) establish complex human pluripotent stem cell-derived intestinal organoids to investigate intestinal inflammation; and ii) implement patient multiorganoid platforms to identify key players in the communication between the inflamed gut and the brain. Unveiling the critical steps that initiate PD may lead to a conceptual leap forward in our understanding of how the gut affects the brain in both health and disease. The novel methodologies that will be developed will also lay the foundations for future interventions aimed at targeting intestinal inflammation in enteric and neurological diseases.
Champ scientifique
- natural sciencesbiological sciencesneurobiology
- medical and health sciencesclinical medicinegastroenterologyinflammatory bowel disease
- medical and health sciencesbasic medicineimmunology
- medical and health sciencesbasic medicineneurologyparkinson
- engineering and technologyother engineering and technologiesmicrotechnologyorgan on a chip
Mots‑clés
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
75654 Paris
France