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: 3881664
• 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/3881664
• 关键词: Alzheimer's disease; Downs syndrome; Huntington's disease; Parkinson's disease; amyloidosis; autoimmune disorder; brain neoplasms; central nervous system disorders; chronic disease /disorder; communicable disease transmission; congenital neuromuscular disorder; cretinisms; degenerative motor system disease; dementia; encephalitis; genetic disorder; human morbidity; human population genetics; human subject; human tissue; laboratory mouse; latent virus infection; molecular pathology; multiple sclerosis; muscular dystrophy; myelinopathy; nervous system disorder epidemiology; nervous system infection; neuromuscular disorder diagnosis; neurotropic virus; partial seizure; posttranslational modifications; progressive multifocal leukoencephalopathy; scrapie; spongiform encephalopathy; subacute sclerosing panencephalitis; virus cytopathogenic effect; virus infection mechanism; virus protein; virus replication

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; autism; SSPE; PML; dialysis encephalopathy; goiterous cretinism; cysticercosis; and intracranial neoplasm. We have defined the transmissible and nontransmissible dementias as cerebral amyloidoses caused by post-translational 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 (X106) 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 nontransmissible brain amylodoses. Our studies focus on the elucidation of the molecular configurational events conferring the property of infectivity on a previously normal host precursor. 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. Conventional viruses causing slow, infectious, degenerative disease are intensely studied to elucidate the neurotropism and mechanism of pathogenesis: retrovirus encephalomylopathies of HTLV-L and HIV (of AIDS),- herpesviruses (HSV, CMV, EB and virus varicella-zoster); papovaviruses (JC),- RSSE; measles; SSPE; and many chronic virus infections of amyloid.

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;孤独症; SSPE; PML;透析 脑病;甲状腺肿性克汀病;囊虫病;颅内 肿瘤。 我们将传染性和非传染性痴呆定义为： 脑淀粉样变性是由a 淀粉样纤维沉积物的特异性宿主前体蛋白。我们现在 认识到慢性非常规病毒引起库鲁-克雅二氏病-瘙痒症， 由正常宿主前体从头形成的复制多肽 蛋白质，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了几点 突变极大地增加了（X106）这种可能性， 自发从头转化为感染性多肽。微生物 现在必须面对一个全新的复制，传染， 非传染性脑淀粉样变性中的致病因子。我们的研究 着重于分子构型事件的阐明 赋予以前正常的宿主传染性 先驱 在正常衰老中，阿尔茨海默病（AD）和唐氏综合征是不同的 宿主前体蛋白（在人的21号染色体上，在小鼠的16号染色体上指定）是 细胞分泌的生长因子抑制剂。翻译后 这种正常前体的降解形成42个氨基酸的淀粉样蛋白 聚合形成淀粉样血管病沉积物的多肽， 淀粉样斑块和神经纤维缠结在老化，AD和唐氏症。这 发生在所有90多岁的人身上。遗传的，有毒的， 感染因素可能加速这种老化的脑淀粉样蛋白沉积。 引起慢性、传染性、变性疾病的常规病毒是 深入研究，以阐明嗜神经性和机制 发病机制：HTLV-L和HIV的逆转录病毒脑脊髓病（ - 疱疹病毒（HSV、CMV、EB和水痘-带状疱疹病毒）; 乳多空病毒（JC）、- RSSE、麻疹、SSPE和许多慢性病毒 淀粉样蛋白感染