Targeting Cytoskeleton Dysregulation in Foamy Phagocytes to Halt Lesion Progression and Promote Remyelination in MS. (R-16094)

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS). While current therapies effectively manage early-stage symptoms, they fail to prevent neurodegeneration in the chronic stages, highlighting the urgent need for novel therapeutic strategies. In MS pathology, macrophages and microglia play a dual role, adopting either a disease-resolving state that promotes repair or a disease-promoting state that drives lesion progression. The latter arises due to excessive myelin-derived lipid accumulation, whereas enhancing lipid processing in phagocytes has been shown to promote the reparative state. Preliminary data on a cytoskeletal modulator DISC1, along with RNA sequencing analyses, suggest that cytoskeletal regulation plays a key role in lipid processing and phagocyte phenotype. Building on this, I hypothesize that excessive myelin uptake disrupts cytoskeletal dynamics, impairing lipid processing and shifting phagocytes toward a lesion-promoting state. To test the hypothesis, I aim to uncover cytoskeletal alterations in lipid-laden phagocytes and their role in shaping phagocyte phenotype using state-of-the-art cell-, and tissue cultures, animal models and human lesions, and innovative lipidomic techniques. This project will provide enhanced insights into the mechanisms governing lipid processing and phagocyte phenotype, particularly linked to cytoskeletal regulation, identifying cytoskeletal modulation as a therapeutic target for MS.

Keywords:Multiple sclerosis, Phagocytes

Disciplines:Lipids, Cytoskeleton