Huntington's disease (HD) is a devastating neurodegenerative disease caused by a polyglutamine expansion mutation in the Huntingtin gene (Ht). The mutant Huntingtin (mHt) exerts dominant toxicity to cause selective neuronal dysfunction and degeneration. Currently, there are very few valid drug targets for HD. One method to identify new drug targets is through genetic modifier studies. Genetic = modifier screenings in Yeast, Drosophila, C. elegans and mammalian cell culture have produced a number of genes that can be manipulated to suppress mutant Huntingtin toxicity. However, the efficacy of these genes to suppress mutant Huntingtin toxicity in the mammalian brain is unclear. This proposal seeks to establish a mouse genetic system that can readily and systematically test genetic suppressors for HD in vivo. Using a relatively novel mouse genetic technology, called Bacterial Artificial Chromosome (BAC) mediated transgenics, we have succeeded in creating novel transgenic mouse models of HI) expressing full-length mutant Huntingtin under the endogenous regulation. Some of these full-length transgenic founders have already demonstrated early and severe motor deficits.
The specific aims of this proposal are to: 1. Characterize the fulfull-lengthC models of HD and select lines suitable for genetic modifier studies. 2. Apply the newly developed rapid BAC modification system to generate mice over expressing two modifier genes and to test their efficacy in suppressing mHt toxicity in the full-length transgenic models. If proven effective, our BAC transgenic System can readily be scaled up to systematically study a large number of putative HD genetic modifiers in vivo. Identification of effective genetic modifiers in mice may provide novel insights into disease pathogenesis and new targets to develop therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS047391-01
Application #
6709446
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Oliver, Eugene J
Project Start
2004-06-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
1
Fiscal Year
2004
Total Cost
$177,388
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Gray, Michelle; Shirasaki, Dyna I; Cepeda, Carlos et al. (2008) Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice. J Neurosci 28:6182-95
Spampanato, J; Gu, X; Yang, X W et al. (2008) Progressive synaptic pathology of motor cortical neurons in a BAC transgenic mouse model of Huntington's disease. Neuroscience 157:606-20
Lobo, Mary Kay; Karsten, Stanislav L; Gray, Michelle et al. (2006) FACS-array profiling of striatal projection neuron subtypes in juvenile and adult mouse brains. Nat Neurosci 9:443-52