Description du projet
Aperçu du rôle du métabolisme et de l’immunité dans la SLA
La sclérose latérale amyotrophique (SLA) est une maladie neurodégénérative qui touche également d’autres systèmes que le système nerveux central. Le projet MegaALS, financé par l’UE, étudie l’hypothèse selon laquelle l’interaction entre le métabolisme, le microbiote intestinal et l’immunité adaptative serait à l’origine de la pathophysiologie de la SLA. Les scientifiques utilisent les données protéomiques, métagénomiques et de réponse immunitaire de patients ayant fait l’objet d’une étude cas-témoins sur la SLA à Stockholm pour valider cette hypothèse. En outre, ils utiliseront un modèle murin de SLA pour tester une stratégie innovante de prévention et de traitement de la maladie combinant un régime alimentaire riche en calories et une transplantation de microbiote fécal provenant de donneurs humains sains. Les résultats permettront de dévoiler les mécanismes physiopathologiques de la SLA et d’identifier de nouvelles cibles préventives et thérapeutiques.
Objectif
Amyotrophic lateral sclerosis (ALS) is a rare but devastating neurodegenerative disorder that in lack of effective treatments leads to death within a few years of diagnosis. ALS is increasingly being recognized as a systemic disease affecting not only the central nervous system but also other physiological aspects. We hypothesize that there is a disease-specific interplay between metabolism, gut microbiome and adaptive immunity, which substantially contributes to the etiopathogenesis of ALS. The overarching aim of this project is therefore to explore such interplay, and to assess the effectiveness of a treatment regimen that specifically targets it. Using a population-based case-control study of ALS in Stockholm, I will first characterize the complex interactions between metabolism, microbiome, and immunity in ALS, through comprehensive proteomic, metagenomic and immune-response profiling. The specificity of these interactions will be tested in contrast to healthy individuals at high risk for ALS (siblings), individuals with similar environmental and lifestyle factors (spouses), and unrelated population-controls. I will then use an established ALS mouse model (SOD1G93A) to understand the usefulness of combining a high-caloric diet with a fecal microbiota transplant from healthy human donors in disease prevention and treatment. To better understand the underlying mechanisms, I will compare microbiome and immune-response profiles before and after the intervention. The proposed research is unique as it 1) combines innovative molecular platforms with a high-quality epidemiological study design, 2) uses a novel strategy of investigating multiple aspects of human physiology, and 3) offers a possibility to directly translate findings between human observational and animal experimental studies. The ultimate goal is to significantly advance our knowledge about ALS as a disease, and more importantly to identify novel and highly warranted preventive and therapeutic targets.
Champ scientifique
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ERC-STG - Starting GrantInstitution d’accueil
17177 Stockholm
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