Background: Aging and unhealthy diet are thought to be factors that contribute to poor regeneration.
Hypothesis: We hypothesize that lipid-sensing nuclear receptor unresponsiveness could be an underlying cause for poor regeneration in aging and obesity.
Strategy: Here, we plan to pursue an integrative and multidisciplinary approach by bringing together genetics, cell biology, lipidomics and imaging in mice.
Age-associated decline in regeneration capacity limits the restoration of tissue functionality in demyelinating diseases such as multiple sclerosis (MS). Yet, the factors responsible for this decline remain only partially understood. Using a toxin-induced demyelination model, we have shown that aged mice fail to resolve the inflammatory response that is induced after myelin injury. Phagocytes accumulate excessive amounts of myelin debris, which triggers cholesterol crystal formation, phagolysosomal membrane rupture and inflammasome activation. Thus, in demyelinating lesions cholesterol-rich myelin debris can overwhelm the efflux capacity of phagocytes, resulting in a transition of free cholesterol into crystals thereby inducing a maladaptive immune response that poses a barrier for tissue regeneration. Nuclear receptors such as the liver X receptor (LXR) and the peroxisome proliferator-activated receptors (PPARs) can function as lipid sensors that respond to cellular lipid levels and elicit gene expression changes to protect cells from lipid overload. In this proposal, we will explore the role of lipid-sensing nuclear receptors as molecular checkpoints in the recovery from demyelinating injury. We hypothesize that lipid-sensing nuclear receptor unresponsiveness could be an underlying cause for poor regeneration in aging and obesity. Specifically, we propose that compensatory signalling pathways suppress lipid-sensing nuclear receptor activation in microglia, thereby preventing their ability to initiate the appropriate genetic programmes required for lipid clearance. We believe that deepening our understanding regarding these cellular networks and molecular checkpoints, will allow us to design new therapeutic strategies on how to promote repair in the CNS.