Project R-14161

Reprogramming macrophage fatty acid metabolism to induce repair in multiple sclerosis (Research)

Foamy myelin-containing macrophages and microglia are major effector cells in chronic demyelinating disorders like multiple sclerosis (MS). They are involved in seemingly opposing processes such as demyelination, neurodegeneration and remyelination. Emerging evidence indicates that faulty metabolic reprogramming upon engulfing excessive amounts of myelin impairs the reparative features of phagocytes. In support of this, my preliminary findings indicate that perturbed fatty acid (FA) metabolism is closely associated with failure of remyelination and the induction of a disease-promoting phenotype of these foamy phagocytes. Based on this, I hypothesize that targeting FA metabolism is a promising therapeutic strategy to drive foamy phagocytes towards a reparative phenotype in demyelinating lesions. To prove this hypothesis, state-of-the-art lipid measurements in combination with metabolic single-cell techniques on human MS lesions and mouse models for remyelination will be applied to determine which FA metabolism enzymes and their pathways are detrimental to proper remyelination. By counteracting or overexpression of the selected enzymes, macrophage reparative capacities and inflammatory activation will be studied in vitro and subsequently validated ex vivo and in vivo. By doing so, this project will unravel the therapeutic potential of targeting macrophage (FA) metabolism in skewing macrophages towards a reparative phenotype to ultimately improve treatments for progressive MS.

01 October 2023 - 30 September 2026