Project R-3656

Cholesterol receptors and transporters as crucial regulators of CNS inflammation (Research)

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) that mainly affects young adults in the prime of their life. No cure is available and therefore MS has a high socio-economic impact. MS is thought to be initiated by autoreactive T cells that instruct phagocytes to degrade the insulating myelin sheath. Various pathological mechanisms determine the subsequent course of disease. Recent findings demonstrate that receptors activated by cholesterol metabolites regulate the expression of genes involved in inflammation and lipid homeostasis. Myelin has an exceptionally high cholesterol content and during demyelination of MS lesions, macrophages take up large quantities of myelin which will modulate their phenotype. Moreover, cholesterol homeostasis in oligodendrocytes is essential for proper myelination. These findings indicate that cholesterol homeostasis plays a key role in autoimmune-induced demyelination in the CNS. In this study we investigate how cholesterol receptors and transporters regulate de- and remyelination in an animal model of MS, and determine which cells and molecular mechanisms are involved. Results obtained will clarify the importance of cholesterol homeostasis in MS and other CNS inflammatory diseases and may reveal new targets for treatment of these diseases.

01 January 2012 - 31 August 2018