The long-term goal of the proposed investigation is to study the pathobiology of genetic neurodegenerative disorders affecting infants and children and to explore the possible therapeutic means of such disorders. Using an authentic murine model of globoid cell leukodystrophy, twitcher mouse, we have been investigating the natural disease processes, with particular focus on cellular reactions associated with the progression of the pathology in the central as well as in the peripheral nervous systems. The studies proposed in this application are a continuation and/or extension of the ongoing studies in my laboratory. Twitcher is a murine model of a genetic demyelinating disease caused by the mutation of the enzyme galactosylceramidase. Although demyelination is a conspicuous histopathology clinical symptoms such as paralysis, opisthotonus and seizures noted in this mutant as well as in GLD patients are clearly attributable to neuronal dysfunction. We plan to investigate 1). the extent of neuronal pathology/dysfunction using the expression of the immediate early genes (IEGs) and/or heat shock proteins (HSPs) as markers and analysis of structural alterations with horseradish peroxidase (HRP) and/or with Golgi preparations. In twitcher, expression of major histocompatibility complex (MHC) class I and II molecules increases with the progression of demyelination. The twitcher mouse with class II-deficient background shows ameriolation of neuropathological lesions (66). 2). We hypothesize that the deficiency of MHC class I molecules also has some beneficial effects to lessen the twitcher pathology and so we will investigate a possible role of MHC class I molecules in twitcher pathology by generating the twitcher mouse with MHC class I deficient background (MHC class I knockout twitcher). And 3). we plan to explore the feasibility of gene transfer as treatment of genetic diseases using twitcher as a model. The studies include generation of transgenic twitcher mouse with the human galactosylceramidase cDNA under the transcriptional control of the myelin basic protein gene as well as the transfer of the human cDNA expression constructs into twitcher cells/tissues with in vitro, in vivo and ex vivo approaches. The result of these studies will be carefully monitored by morphology, immunocytochemistry and mRNA expression of myelin proteins assay of galactosylceramidase activity, analysis of the level of psychosine etc. For the treatment of genetic diseases, transfer of the missing gene into appropriate tissues/cells is an obvious treatment of choice. However, in practice, there are many problems in transferring genes, in particular for the treatment of genetic diseases affecting the nervous system. Therefore, well controlled studies using an established animal model of the disease is essential before any attempt of gene therapy in human patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS024453-15
Application #
6165408
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Program Officer
Spinella, Giovanna M
Project Start
1986-05-01
Project End
2001-07-31
Budget Start
2000-03-01
Budget End
2001-07-31
Support Year
15
Fiscal Year
2000
Total Cost
$328,936
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Hiremath, Meenaxi M; Chen, Vivian S; Suzuki, Kinuko et al. (2008) MHC class II exacerbates demyelination in vivo independently of T cells. J Neuroimmunol 203:23-32
Kagitani-Shimono, Kuriko; Mohri, Ikuko; Yagi, Takashi et al. (2008) Peripheral neuropathy in the twitcher mouse: accumulation of extracellular matrix in the endoneurium and aberrant expression of ion channels. Acta Neuropathol 115:577-87
Mohri, Ikuko; Taniike, Masako; Taniguchi, Hidetoshi et al. (2006) Prostaglandin D2-mediated microglia/astrocyte interaction enhances astrogliosis and demyelination in twitcher. J Neurosci 26:4383-93
Mohri, Ikuko; Taniike, Masako; Okazaki, Issei et al. (2006) Lipocalin-type prostaglandin D synthase is up-regulated in oligodendrocytes in lysosomal storage diseases and binds gangliosides. J Neurochem 97:641-51
Kagitani-Shimono, K; Mohri, I; Oda, H et al. (2006) Lipocalin-type prostaglandin D synthase (beta-trace) is upregulated in the alphaB-crystallin-positive oligodendrocytes and astrocytes in the chronic multiple sclerosis. Neuropathol Appl Neurobiol 32:64-73
Langmade, S Joshua; Gale, Sarah E; Frolov, Andrey et al. (2006) Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann-Pick C disease. Proc Natl Acad Sci U S A 103:13807-12
Yagi, Takashi; Matsuda, Junko; Tominaga, Kumiko et al. (2005) Hematopoietic cell transplantation ameliorates clinical phenotype and progression of the CNS pathology in the mouse model of late onset Krabbe disease. J Neuropathol Exp Neurol 64:565-75
Wu, Yun-Ping; Mizukami, Hiroki; Matsuda, Junko et al. (2005) Apoptosis accompanied by up-regulation of TNF-alpha death pathway genes in the brain of Niemann-Pick type C disease. Mol Genet Metab 84:9-17
Takikita, Shoichi; Fukuda, Takahiro; Mohri, Ikuko et al. (2004) Perturbed myelination process of premyelinating oligodendrocyte in Niemann-Pick type C mouse. J Neuropathol Exp Neurol 63:660-73
Saito, Yuko; Suzuki, Kinuko; Hulette, Christine M et al. (2004) Aberrant phosphorylation of alpha-synuclein in human Niemann-Pick type C1 disease. J Neuropathol Exp Neurol 63:323-8

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