DEVELOPMENT OF CELLULAR AND ANIMAL MODELS FOR HUNTINGTONS DISEASE

亨廷顿病细胞和动物模型的开发

• 批准号: 6162596
• 负责人: D A TAGLE
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162596
• 关键词: Huntington's disease; artificial chromosomes; disease /disorder model; genetically modified animals; glutaminase; laboratory mouse; model design /development; molecular cloning; molecular pathology; nucleic acid repetitive sequence; protein glutamine gamma glutamyltransferase; protein structure; protein structure function; transfection

HD is an autosomal dominant, progressive, neurodegenerative disorder with onset generally in midlife. Clinical manifestations of HD include chorea, dementia and other neuropsychiatric disturbances with onset generally in mid-life though juvenile forms of the disease exist. The identification of the HD gene in an international collaboration including this PI in 1993, showed a polymorphic tandem (CAG)n trinucleotide repeat in exon 1 where the normal repeat size range is from 11 to 34 copies. When the repeats exceed 40, HD is the consequence. The repeats are encoded into polyglutamines in the 348 kD huntingtin protein. We have generated full length normal and mutated cDNA constructs for expression in neuronal cell lines in order to elucidate the "gain of function" effect of the poly-Q expanded protein. We have also made a series of mouse HD transgenic lines with varying repeat sizes (16, 48 and 89 CAGs) and are studying them for behavioral phenotype and neuropathology.

HD是一种常染色体显性、进行性、神经退行性疾病， 一般在中年发病。HD的临床表现包括舞蹈症、 痴呆和其他神经精神障碍，起病一般在 这种疾病虽然是以青少年的形式存在，但在中年仍然存在。身份识别 在一个国际合作中的HD基因，包括这个PI在 1993年，在外显子1中发现了一个多态串联(CAG)n三核苷酸重复序列 其中正常的重复大小范围是11到34个拷贝。当 重复次数超过40次，后果就是高清。重复序列被编码成 348 kD亨廷顿蛋白中的多谷氨酸。我们已经生成了完整的 长度正常和突变的cDNA构建物在神经细胞中的表达 为了阐明多聚Q的“功能增益”效应 膨化蛋白质。我们还建立了一系列的小鼠HD转基因株系 具有不同的重复大小(16、48和89个CAG)，并正在研究它们 行为表型和神经病理学。