The overall objective of this project is to elucidate the pathogenic mechanisms underlying autoimmune demyelinative neuropathy. Special attention will be directed at the role of a new class of sulfated glucuronic acid containing glycolipids (SGGLs) which are primarily localized in peripheral nervous system (PNS) myelin, axolemma, and Schwann cells in the disease processes. These glycolipids share a common carbohydrate epitope with myelin-associated glycoprotein (MAG) and a number of cell adhesion molecules in the nervous and immune systems. Although the involvement of these glycoconjugates in the pathogenesis of this type of peripheral neuropathy is still obscure, there is increasing evidence implicating that the glycolipids may serve as important target antigens for the circulating immunoglobulins in patients with demyelinating neuropathy. In this project, we will continue to characterize additional immunoreactive glycolipid structures and define their cellular and subcellular localization in order to seek the basis for the differential clinical manifestations in this disease. Previous studies from this laboratory have suggested an antibody-mediated complement-dependent cytotoxicity mechanism for this type of disorder. We will further define the specificity of the pathogenic antibodies and the complement components in experimental models of this disease. Since SGGLs are apparently expressed in endothelial cells which constitute the major anatomical structure of blood-brain and blood- nerve barriers, we hypothesize that the circulating antibodies and blood components may gain entrance to the nerve by attacking endothelial cell- bound SGGLs, causing changes in barrier function. The role of SGGLs in the maintenance of the functional integrity of the vascular system will be investigated in in vivo and in vitro systems. Finally and most importantly we will evaluate the safety and efficacy of a therapeutic approach by selective extracorporeal removal of pathogenic immunoglobulins in an animal model of neuropathy. Our long-term goal is to apply the knowledge gained through this study for the effective treatment of other related autoimmune neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS026994-06
Application #
3413134
Study Section
Neurology C Study Section (NEUC)
Project Start
1988-06-01
Project End
1996-05-31
Budget Start
1993-06-01
Budget End
1994-05-31
Support Year
6
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Itokazu, Yutaka; Wang, Jing; Yu, Robert K (2018) Gangliosides in Nerve Cell Specification. Prog Mol Biol Transl Sci 156:241-263
Itokazu, Yutaka; Tsai, Yi-Tzang; Yu, Robert K (2017) Epigenetic regulation of ganglioside expression in neural stem cells and neuronal cells. Glycoconj J 34:749-756
Tsai, Yi-Tzang; Itokazu, Yutaka; Yu, Robert K (2016) GM1 Ganglioside is Involved in Epigenetic Activation Loci of Neuronal Cells. Neurochem Res 41:107-15
Yu, Robert K; Usuki, Seigo; Itokazu, Yutaka et al. (2016) Novel GM1 ganglioside-like peptide mimics prevent the association of cholera toxin to human intestinal epithelial cells in vitro. Glycobiology 26:63-73
Koon, Noah A; Itokazu, Yutaka; Yu, Robert K (2015) Ganglioside-Dependent Neural Stem Cell Proliferation in Alzheimer's Disease Model Mice. ASN Neuro 7:
Itokazu, Yutaka; Yu, Robert K (2014) Amyloid ?-peptide 1-42 modulates the proliferation of mouse neural stem cells: upregulation of fucosyltransferase IX and notch signaling. Mol Neurobiol 50:186-96
Usuki, Seigo; O'Brien, Dawn; Rivner, Michael H et al. (2014) A new approach to ELISA-based anti-glycolipid antibody evaluation of highly adhesive serum samples. J Immunol Methods 408:52-63
Parameswaran, Reshmi; Lim, Min; Arutyunyan, Anna et al. (2013) O-acetylated N-acetylneuraminic acid as a novel target for therapy in human pre-B acute lymphoblastic leukemia. J Exp Med 210:805-19
Galban-Horcajo, F; Fitzpatrick, A M; Hutton, A J et al. (2013) Antibodies to heteromeric glycolipid complexes in multifocal motor neuropathy. Eur J Neurol 20:62-70
Wang, Jing; Yu, Robert K (2013) Interaction of ganglioside GD3 with an EGF receptor sustains the self-renewal ability of mouse neural stem cells in vitro. Proc Natl Acad Sci U S A 110:19137-42

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