Alexander disease is a rare and generally fatal disorder of the CNS that primarily affects young children. Recent genetic studies have identified heterozygous missense mutations in the astrocyte intermediate filament glial fibrillary acidic protein (GFAP) as the major cause of this disease. To begin a search for potential treatments of this devastating disease, the investigator proposes to screen a library of drugs that are already FDA-approved to identify compounds that suppress expression of GFAP. He will evaluate changes in GFAP expression at the level of both protein and gene transcription, in glioma cell lines (Specific Aim 1), primary cultures of astrocytes (Specific Aim 2), and organotypic explant cultures of spinal cord (Specific Aim 3). In future years using mice that express the same mutant GFAPs found in human patients (generated as part of another project) can then be tested candidate drugs identified as part of this screen. By restricting the focus to the FDA-approved list, successful identification of GFAP-suppressing drugs could offer immediate therapeutic benefit to Alexander disease patients.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
5R03HD046599-02
Application #
7066650
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Oster-Granite, Mary Lou
Project Start
2005-06-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2008-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$71,040
Indirect Cost
Name
University of Wisconsin Madison
Department
Pediatrics
Type
Other Domestic Higher Education
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Messing, Albee; Brenner, Michael; Feany, Mel B et al. (2012) Alexander disease. J Neurosci 32:5017-23
Cho, Woosung; Brenner, Michael; Peters, Noel et al. (2010) Drug screening to identify suppressors of GFAP expression. Hum Mol Genet 19:3169-78
Messing, Albee; LaPash Daniels, Christine M; Hagemann, Tracy L (2010) Strategies for treatment in Alexander disease. Neurotherapeutics 7:507-15
Cho, Woosung; Hagemann, Tracy L; Johnson, Delinda A et al. (2009) Dual transgenic reporter mice as a tool for monitoring expression of glial fibrillary acidic protein. J Neurochem 110:343-51