CHRONIC CNS DISEASE STUDIES--SLOW, LATENT AND TEMPERATE VIRUS INFECTIONS

慢性中枢神经系统疾病研究——缓慢、潜伏和温带病毒感染

• 批准号: 3860741
• 负责人: D CARLETON GAJDUSEK
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 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/3860741
• 关键词: Alzheimer's disease; Downs syndrome; Huntington's disease; Parkinson's disease; amyotrophic lateral sclerosis; ataxia; autism; bipolar depression; brain neoplasms; cerebral palsy; child (0-11); chronic disease /disorder; cretinisms; degenerative motor system disease; dementia; encephalitis; epilepsy; human subject; human tissue; interview; latent virus infection; magnetic resonance imaging; molecular genetics; molecular pathology; multiple sclerosis; nervous system infection; posttranslational modifications; schizophrenia; virus cytopathogenic effect; virus infection mechanism

Studies focus on causes and pathogenesis of chronic degenerative CNS disorders with emphasis on MS; Parkinson's, Pick's, Huntington's and Alzheimer's diseases; ALS/PD of Western Pacific; supranuclear palsy; other presenile dementias; spinocerebellar ataxias; epilepsy; chronic encephalitis with focal epilepsy; Viliuisk encephalopathy; muscular dystrophies; chronic schizophrenia; bipolar psychoses, autism; SSPE; PML; dialysis encephalopathy; goiterous cretinism; cysticercosis; and intracranial neoplasms. We have defined the transmissible and nontransmissible dementias as brain amyloidoses caused by posttranslational modification of a specific host precursor protein to amyloid fibril deposits. We now recognize the slow unconventional viruses causing kuru-CJD-scrapie as replicating polypeptides formed de novo from a normal host precursor protein, specified on chromosome 20 in man and 2 in mice. The molecular elucidation of the spontaneous configurational change to infectivity, basically a crystallographic problem, is now becoming our major target. Molecular genetic analysis of familial CJD already indicates several point mutations which enormously increase (xl0(6))the probability of this spontaneous de novo conversion to an infectious polypeptide. Microbiology must now contend with a totally new paradigm for replicating, infectious, pathogenic agents in the transmissible brain amylodoses. Our studies focus on the elucidation of the molecular configurational events conferring the property of infectivity on a previously normal host precursor using MRI to elucidate the change in configuration which occurs as transmissibility is produced. In normal aging, Alzheimer's disease (AD), and Down's syndrome a different host precursor protein (specified on chromosome 21 in man, 16 in mice) is a cell-excreted inhibitor of growth factors. Post- translational degradation of this normal precursor forms the 42 amino acid amyloid polypeptide which polymerizes to form the deposits of amyloid angiopathy, amyloid plaques and neurofibrillary tangles in aging, AD and Down's. This occurs in all individuals who reach their 90s. Genetic, toxic, and infectious factors may accelerate this aging brain amyloid deposition.

中枢神经系统慢性退行性变的病因和发病机制 以MS为重点的疾病;帕金森氏症、皮克氏症、亨廷顿氏症和 阿尔茨海默病;西太平洋ALS/PD;核上性麻痹; 其他早老性痴呆;脊髓小脑共济失调;癫痫;慢性 脑炎伴局灶性癫痫;维留伊斯克脑病;肌性 营养不良;慢性精神分裂症;双相性精神病，孤独症; SSPE; PML; 透析性脑病;甲状腺肿性克汀病;囊虫病;和 颅内肿瘤 我们已经将传染性和非传染性痴呆定义为脑 由特定宿主的翻译后修饰引起的淀粉样变性 淀粉样纤维沉积的前体蛋白。 我们现在认识到 引起库鲁-克雅二氏病-羊瘙痒病的非常规病毒 由正常宿主前体蛋白从头形成的多肽， 在人的20号染色体和小鼠的2号染色体上特异性。 分子 阐明感染性的自发构型变化， 基本上是一个晶体学问题，现在成为我们的主要目标。 家族性克雅氏病的分子遗传学分析已经表明， 点突变极大地增加了（xl 0（6））的概率， 自发从头转化为感染性多肽。 微生物学现在必须与一个全新的范式作斗争， 在可传播的大脑中复制，传染，致病因子 淀粉样变性 我们的研究集中在分子的阐明 配置事件赋予一个人传染性的属性， 使用MRI来阐明先前正常的宿主前体的变化 当产生传输性时发生的配置。 在正常的衰老过程中，阿尔茨海默病（AD）和唐氏综合征（Down's syndrome）是一种 不同的宿主前体蛋白（在人的21号染色体上特异性，16 在小鼠中）是细胞分泌的生长因子抑制剂。 后 这种正常前体的翻译降解形成42个氨基酸 酸性淀粉样多肽，其聚合形成 淀粉样血管病、淀粉样斑块和衰老中的神经纤维缠结， AD和Down's 这发生在所有达到90岁的人身上。 遗传、毒性和感染因素可能会加速这种大脑老化 淀粉样沉积