The ultimate goals of this project are to understand the causes and consequences of the expression of the expanded (CAG)n triplet repeat in the Huntington's disease gene and to determine whether this knowledge can be applied to develop an effective mode of therapy for the disorder. It is not clear how expansion of this trinucleotide repeat sequence can lead to the premature death of a specific subset of neurons. Furthermore, the functional characteristics of the protein encoded by the normal IT15 gene must be defined. Man does not constitute a manipulable experimental system in which these issues can be explored and there is presently no genetic animal model of HD. Consequently, we plan to take advantage of the advances which have been made in introducing foreign genes into the mouse to create a collection of transgenic mice that will permit the exploration of three critical issues, the instability of the (CAG)n mutation ,in the mouse, the function of the normal HD allele via the phenotype of a null mutation, and the phenotype produced by the expanded (CAG)n repeat, either in an introduced human gene or appropriately positioned in the endogenous mouse gene. Mice that express human HD constructs and the altered mouse homologue will be bred to establish a genetic animal model of HD which will be subjected to detailed analysis. This project is a challenging undertaking which, like the previous successes in linkage mapping and subsequent cloning of the HD gene, could have a revolutionary impact on all aspects of HD research. If the mouse model expresses significant neuropathology, it would permit a much more detailed analysis of the anatomical and biochemical effects of the expanded (CAG)n IT15 triplet repeat, the genetics of its expression, and its relationship to the excitotoxin hypothesis of neuronal death, while providing an accurate system in which therapeutic approaches could be tested. However, even if mice expressing the HD gene fail to express any abnormality, they will merit continued study to determine the basis for their lack of susceptibility to HD, which might provide a clue to a potential treatment in man.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS032765-04
Application #
2037786
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Program Officer
Oliver, Eugene J
Project Start
1994-05-01
Project End
2001-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Ramos, Eliana Marisa; Kovalenko, Marina; Guide, Jolene R et al. (2015) Chromosome substitution strain assessment of a Huntington's disease modifier locus. Mamm Genome 26:119-30
Biagioli, Marta; Ferrari, Francesco; Mendenhall, Eric M et al. (2015) Htt CAG repeat expansion confers pleiotropic gains of mutant huntingtin function in chromatin regulation. Hum Mol Genet 24:2442-57
Ramos, Eliana Marisa; Gillis, Tammy; Mysore, Jayalakshmi S et al. (2015) Prevalence of Huntington's disease gene CAG trinucleotide repeat alleles in patients with bipolar disorder. Bipolar Disord 17:403-8
Labadorf, Adam; Hoss, Andrew G; Lagomarsino, Valentina et al. (2015) RNA Sequence Analysis of Human Huntington Disease Brain Reveals an Extensive Increase in Inflammatory and Developmental Gene Expression. PLoS One 10:e0143563
Carroll, Jeffrey B; Deik, Amy; Fossale, Elisa et al. (2015) HdhQ111 Mice Exhibit Tissue Specific Metabolite Profiles that Include Striatal Lipid Accumulation. PLoS One 10:e0134465
Ramos, Eliana Marisa; Gillis, Tammy; Mysore, Jayalakshmi S et al. (2015) Haplotype analysis of the 4p16.3 region in Portuguese families with Huntington's disease. Am J Med Genet B Neuropsychiatr Genet 168B:135-43
Galkina, Ekaterina I; Shin, Aram; Coser, Kathryn R et al. (2014) HD CAGnome: a search tool for huntingtin CAG repeat length-correlated genes. PLoS One 9:e95556
Hoss, Andrew G; Kartha, Vinay K; Dong, Xianjun et al. (2014) MicroRNAs located in the Hox gene clusters are implicated in huntington's disease pathogenesis. PLoS Genet 10:e1004188
Zhang, Bin; Gaiteri, Chris; Bodea, Liviu-Gabriel et al. (2013) Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 153:707-20
Ramos, Eliana Marisa; Latourelle, Jeanne C; Gillis, Tammy et al. (2013) Candidate glutamatergic and dopaminergic pathway gene variants do not influence Huntington's disease motor onset. Neurogenetics 14:173-9

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