Glycosphingolipids (GSLs) are enriched in plasma membranes and comprise the gangliosides and the neutral glycosphingolipids. The infantile and juvenile forms of the ganglioside storage diseases (GM1 and GM2 gangliosidoses) present with severe mental and motor degeneration within the first few years of birth due largely to ganglioside accumulation in the brain. Since complex GSLs are actively synthesized during early stages of mammalian embryonic development, neuropathology associated with ganglioside accumulation will commence during fetal development and will worsen in the postnatal brain. An effective treatment strategy would therefore require aggressive early intervention. The objective of this application is to evaluate the effects of NB-DGJ on glycosphingolipid metabolism during embryonic and postnatal brain development. NB-DGJ (N-butyldeoxygalactonojirimycin) is a water-soluble inhibitor of the ceramide specific glucosyltransferase, a key enzyme for glycosphingolipid (GSL) biosynthesis. Preliminary findings indicate that NB-DGJ can inhibit GSL biosynthesis without altering viability or morphogenesis in the organogenesis stage cultured whole mouse embryo. Moreover, our collaborators showed that a structural isomer of NB-DGJ could prevent lysosomal storage in adult Tay-Sachs mice and could reduce neurological abnormalities in juvenile Sandhoff disease mice. There have been no prior studies on the effects of NB-DGJ on the GSL composition and morphogenesis in the mammalian embryo growing in utero or during early postnatal brain development. This research will examine for the first time: 1) the effects of NB-DGJ on the GSL composition of embryonic and postnatal brains in mouse models of the gangliosidoses, 2) the influence of NB-DGJ treatment on embryonic and postnatal brain development, and 3) whether embryonic and postnatal NB-DGJ treatment has long-lasting effects on brain development, neurochemistry, and behavior. The content and distribution of GSLs will be measured in neural and nonneural tissues of control and NB-DNJ-treated mice. Embryonic and postnatal brain development will be assessed from morphological, histological, and biochemical measurements. Since there are no effective treatments for human ganglioside storages disease, the proposed research could offer a novel therapy for the early intervention of these neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD039722-04
Application #
6685220
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Oster-Granite, Mary Lou
Project Start
2001-03-01
Project End
2004-11-30
Budget Start
2003-12-01
Budget End
2004-11-30
Support Year
4
Fiscal Year
2004
Total Cost
$205,878
Indirect Cost
Name
Boston College
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
045896339
City
Chestnut Hill
State
MA
Country
United States
Zip Code
02467
Seyfried, Thomas N; Flores, Roberto; Poff, Angela M et al. (2015) Metabolic therapy: a new paradigm for managing malignant brain cancer. Cancer Lett 356:289-300
Mantis, John G; Meidenbauer, Joshua J; Zimick, Nicholas C et al. (2014) Glucose reduces the anticonvulsant effects of the ketogenic diet in EL mice. Epilepsy Res 108:1137-44
Seyfried, Thomas N; Flores, Roberto E; Poff, Angela M et al. (2014) Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis 35:515-27
Seyfried, Thomas N; Huysentruyt, Leanne C (2013) On the origin of cancer metastasis. Crit Rev Oncog 18:43-73
Seyfried, Thomas N; Marsh, Jeremy; Shelton, Laura M et al. (2012) Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer? Epilepsy Res 100:310-26
Huysentruyt, Leanne C; Akgoc, Zeynep; Seyfried, Thomas N (2011) Hypothesis: are neoplastic macrophages/microglia present in glioblastoma multiforme? ASN Neuro 3:
Seyfried, Thomas N; Kiebish, Michael A; Marsh, Jeremy et al. (2011) Metabolic management of brain cancer. Biochim Biophys Acta 1807:577-94
Denny, Christine A; Desplats, Paula A; Thomas, Elizabeth A et al. (2010) Cerebellar lipid differences between R6/1 transgenic mice and humans with Huntington's disease. J Neurochem 115:748-58
Huysentruyt, Leanne C; Seyfried, Thomas N (2010) Perspectives on the mesenchymal origin of metastatic cancer. Cancer Metastasis Rev 29:695-707
Seyfried, B Thomas N; Kiebish, Michael; Marsh, Jeremy et al. (2009) Targeting energy metabolism in brain cancer through calorie restriction and the ketogenic diet. J Cancer Res Ther 5 Suppl 1:S7-15

Showing the most recent 10 out of 35 publications