Kurzfassung

G-protein-coupled receptors (GPCRs) have long been known to mediate the effects of various immunomodulatory molecules, but we are only beginning to understand their exact function in neuroinflammatory conditions such as multiple sclerosis (MS). The aim of this project is therefore to define the role of specific GPCRs and G-protein-mediated signaling pathways in immune cells in neuroinflammation. In the first part of the project, we will address the role of the G-protein families Gq/11 and...G-protein-coupled receptors (GPCRs) have long been known to mediate the effects of various immunomodulatory molecules, but we are only beginning to understand their exact function in neuroinflammatory conditions such as multiple sclerosis (MS). The aim of this project is therefore to define the role of specific GPCRs and G-protein-mediated signaling pathways in immune cells in neuroinflammation. In the first part of the project, we will address the role of the G-protein families Gq/11 and G12/13 in lymphocytes and myeloid cells during experimental allergic encephalomyelitis (EAE), the mouse model of MS. Preliminary data obtained in T cell-specific G12/13-deficient mice point to an immunomodulatory effect of this G-protein family in EAE, with a neuroprotective effect of G12/13 deficiency in the late phase of the disease. We plan to dissect the mechanisms underlying this finding, especially with respect to T cell trafficking, differentiation and survival. In parallel, we will characterize the role of G12/13 and Gq/11 in myeloid cells in EAE, with a special focus on cell adhesion, migration, and activation. In the second and third part of the project, we will investigate the role of two recently deorphanized GPCRs in neuroinflammation, EBI2 (GPR183) and GPR109A (HCA2, Niacr1). EBI2 is expressed in the majority of peripheral CD4+ T cells, and preliminary data from our lab show that EBI2-deficient mice display normal T- cell development and Th1/Th17 polarization, but are significantly protected from EAE. We will here investigate the molecular mechanisms underlying the role of EBI2 in EAE, in particular with respect to the role of its newly discovered ligand, 7alpha,25-dihydroxycholesterol, in the regulation of T cells trafficking to CNS lesions. In parallel to these studies we will investigate the mechanism of action of dimethyl fumarate, a substance that is currently in phase III clinical testing for MS treatment, and nicotinic acid, a drug that was shown to have beneficial effects in murine EAE. Both substances are agonists at receptor GPR109A, and we will here use GPR109A-deficient mice and GPR109A reporter mice to clarify whether this receptor mediates the therapeutic effects of the two drugs, and if so, which downstream signaling cascades are involved. Taken together, the aim of this project is to fully understand the role of the G-protein families Gq/11 and G12/13, as well as the receptors GPR109A and EBI2 in EAE and MS, with the long-term goal to elucidate and define potential targets for the treatment or prevention of neuroinflammation. » weiterlesen» einklappen