Multiple sclerosis (MS) is a chronic autoimmune disease characterized by the degradation of CNS myelin. The etiology of the disease is still unknown; both genetic and environmental factors have been implicated. Oligodendrocyte apoptosis may represent an initiating event in MS, with improper removal of apoptotic cell bodies and released myelin fueling the immune response. Low density lipoprotein receptor-related protein-1 (LRP-1) is a cellular receptor, which functions in endocytosis and cell signaling. We have demonstrated that LRP-1 is a key endocytic receptor for myelin in vitro. LRP-1 also inhibits the inflammatory response by controlling the NF?B pathway. We, therefore, hypothesize that LRP-1 could be directly involved in regulation of the development and/or progression of MS. We will test this hypothesis by a combination of in vivo and in vitro experiments. As complete LRP-1 deficiency is lethal, the role of LRP-1 in a mouse EAE model will be determined using mice with conditional LRP-1 deficiency in the myeloid lineage. Our preliminary results suggest that LRP-1 deficiency in this model leads to a significant increase in EAE symptoms. Effector functions of LRP-1- deficient macrophages will be characterized. Finally, we propose to identify LRP-1 ligands in myelin preparations, using a proteomics discovery approach. This research grant proposal should provide the basis for understanding the function of LRP-1 in MS and for potential development of novel therapeutics for MS.
Multiple sclerosis (MS) is a chronic disease characterized by the immune system attack on myelin sheath, which is necessary for proper brain function. This proposal is focused on a cell protein, LRP- 1, which we show is important in the clearance of degraded myelin, and controls of the immune response. We hypothesize that LRP-1 regulates the sequence of events leading to MS development.
We aim to identify the mechanisms by which LRP-1 functions in MS, with potential of discovering ways leading towards development of novel treatments for MS patients.
|Stiles, Travis L; Dickendesher, Travis L; Gaultier, Alban et al. (2013) LDL receptor-related protein-1 is a sialic-acid-independent receptor for myelin-associated glycoprotein that functions in neurite outgrowth inhibition by MAG and CNS myelin. J Cell Sci 126:209-20|
|Fernandez-Castaneda, Anthony; Arandjelovic, Sanja; Stiles, Travis L et al. (2013) Identification of the low density lipoprotein (LDL) receptor-related protein-1 interactome in central nervous system myelin suggests a role in the clearance of necrotic cell debris. J Biol Chem 288:4538-48|