DEVELOPMENT OF CELLULAR AND ANIMAL MODELS FOR HUNTINGTONS DISEASE

亨廷顿氏病（HD）是一种常染色体显性的神经退行性疾病

Huntington's Disease (HD) is an autosomal dominant, neurodegenerative disorder which is associated with CAG trinucleotide repeat expansions. The polymorphic (CAG)n trinucleotide repeat in HD ranges from 6 to 34 copies in normal individuals but is pathogenic when the repeats expand to a range of 35 to 126. This repeat coding for polyglutamines is located within the coding sequence of the 348 kD HD protein. The HD message and protein are widely expressed leaving unexplained its specific neuropathology in the basal ganglia. In order to fully understand the pathogenesis of HD, we are conducting studies with the following specific aims: 1) to determine the structure of the HD protein purified from a baculovirus expression system, 2) to develop transgenic mice using full length HD cDNA that contains either 16, 48 and 89 CAG repeats, 3) to develop YAC transgenic mice using a 350 kb YAC that contains the HD genomic locus and which has been retrofitted with 48 repeats, 4) to examine the effects of various CAG repeat sizes in the rate of proliferation, differentiation and apoptosis of HD-/- ES cells that have been transfected with HD expression constructs containing various CAG repeat lengths, and 5) to examine the effects of transglutaminase (TGase) in the disease process by co-transfecting a TGase expression construct with the HD full length clones into the HD-/- ES cells. These studies will provide important clues to the function of the HD protein, and its role in neuropathology, behavior and trinucleotide repeat instability in HD.