Huntington's Disease (HD) is an autosomal dominant neurodegenerative disorder characterized by chorea, dementia and personality disorder. Manifestations typically begin in middle-age and symptoms are progressive. There is no effective treatment for HD which follows an inexorable course leading first to total debilitation and then to death some 15 to 20 years after onset. HD places enormous economic and psychological burdens on its victim, the family and society as a whole. The Huntington's Disease Center Without Walls is a basic research center which has as its primary goals the discovery of the genetic defect causing HD, the elucidation of the mechanisms whereby it produces the clinical and pathologic features of the disorder, and the development of effective approaches to therapy. Now entering its tenth year, the Center is multidisciplinary, encompassing in a single cooperative program a broad range of research approaches including genetics, epidemiology, biochemistry, and neuroanatomy. This has been an exceedingly successful program which has significantly enhanced our knowledge of HD and altered the course of HD research. HD Center investigators have made seminal contributions to the genetics and epidemiology of HD, to the biochemical and neuropathological features of the disease, and to the organization of the basal ganglia. In particular, the dramatic demonstration in HD of the power of genetic linkage analysis with DNA markers helped to revolutionize the study of inherited human disease. The present renewal application reflects the high level of continued commitment of the investigators to achieving the Center's goals. Four projects and two core facilities are continued from the past grant period and two exciting new projects have been added. The proposed projects will attempt to define the molecular defect in HD (#1), to explore factors modifying its expression (#2), to investigate biochemical alterations in HD brain (E3), to study the response of surviving neurons to local cell death (#4), to create a genetic mouse model of HD (#5) and to generate a primate lesion model for the disorder (#6). The Center comprises a team of highly interactive investigators with a unique combination of expertise and considerable experience in HD. We are confident that the next five years will see tremendous strides towards achieving our goals of understanding the nature and consequences of the genetic defect, and of being able to provide an effective treatment for HD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS016367-15
Application #
2263000
Study Section
Neurological Disorders Program Project Review B Committee (NSPB)
Project Start
1980-07-01
Project End
1995-06-30
Budget Start
1994-07-01
Budget End
1995-06-30
Support Year
15
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Keum, Jae Whan; Shin, Aram; Gillis, Tammy et al. (2016) The HTT CAG-Expansion Mutation Determines Age at Death but Not Disease Duration in Huntington Disease. Am J Hum Genet 98:287-98
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
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
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
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
Lee, Jong-Min; Galkina, Ekaterina I; Levantovsky, Rachel M et al. (2013) Dominant effects of the Huntington's disease HTT CAG repeat length are captured in gene-expression data sets by a continuous analysis mathematical modeling strategy. Hum Mol Genet 22:3227-38
Ramos, Eliana Marisa; Latourelle, Jeanne C; Lee, Ji-Hyun et al. (2012) Population stratification may bias analysis of PGC-1? as a modifier of age at Huntington disease motor onset. Hum Genet 131:1833-40
Chiang, Colby; Jacobsen, Jessie C; Ernst, Carl et al. (2012) Complex reorganization and predominant non-homologous repair following chromosomal breakage in karyotypically balanced germline rearrangements and transgenic integration. Nat Genet 44:390-7, S1
Lee, Jong-Min; Gillis, Tammy; Mysore, Jayalakshmi Srinidhi et al. (2012) Common SNP-based haplotype analysis of the 4p16.3 Huntington disease gene region. Am J Hum Genet 90:434-44
Lee, Ji-Hyun; Lee, Jong-Min; Ramos, Eliana Marisa et al. (2012) TAA repeat variation in the GRIK2 gene does not influence age at onset in Huntington's disease. Biochem Biophys Res Commun 424:404-8

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