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

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: 2579500
• 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/2579500
• 关键词: Alzheimer's disease; Downs syndrome; Huntington's disease; Parkinson's disease; X ray crystallography; aging; amyloidosis; amyotrophic lateral sclerosis; cerebellar ataxia /dyskinesia; cerebral degeneration; chronic disease /disorder; circular dichroism; dementia; human subject; human tissue; interview; latent virus infection; molecular pathology; multiple sclerosis; nervous system disorder epidemiology; neurotropic virus; posttranslational modifications; virus infection mechanism

Studies focus on the causes and pathogenesis of chronic degenerative CNS disorders with emphasis on multiple sclerosis (MS); Parkinson's, Pick's, 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 conformational 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 (x10 ) 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 amyloidoses. Our studies focus on the elucidation of the molecular configurational events conferring the property of infectivity on a previously normal host precursor using CD spectrophotometry, high-voltage EM, MRI to elucidate the change in conformation 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 (protease nexin II). Posttranslational 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.

慢性退行性中枢神经系统的病因和发病机制研究 以多发性硬化症(MS)为重点的疾病；帕金森氏症、Pick‘s、 核上性瘫痪；其他老年前期痴呆；脊髓小脑性共济失调； 癫痫；慢性脑炎伴局灶性癫痫；维柳斯克 脑病；肌营养不良；慢性精神分裂症；双相情感障碍 精神病，自闭症；SSPE；PML；透析性脑病，甲状腺肿 克汀病；囊虫病；以及颅内肿瘤。我们已经定义了 脑淀粉样变性引起的遗传性和非遗传性痴呆 通过对特定宿主前体蛋白的翻译后修饰 淀粉样原纤维沉积。我们现在认识到缓慢的非传统 引起库鲁-CJD-瘙痒病的病毒，因为复制多肽形成了 Novo来自一种正常的宿主前体蛋白，在20号染色体上指定 人和2只小鼠。自发性的分子阐释 构象变化到感染性，基本上是结晶学 问题，现在正成为我们的主要目标。分子遗传学分析 家族性CJD的基因突变已经表明有几个点突变 极大地增加(X10)这种自发从头开始的概率 转化为具有感染性的多肽。微生物学现在必须争辩说 以一种全新的模式复制、传染、致病 遗传性脑淀粉样变性的药物。我们的研究重点是 分子构型事件的阐明 用CD研究先前正常寄主前体的感染性 用分光光度法、高压电子显微镜、磁共振成像来阐明 当遗传性产生时发生的构象。正常情况下 老龄化、阿尔茨海默病(AD)和唐氏综合症--不同的宿主 前体蛋白(人类为21号染色体，小鼠为16号染色体)是一种 细胞分泌的生长因子抑制物(蛋白酶Nexin II)。 这种正常前体的翻译后降解形成42-氨基 一种酸性淀粉样多肽，聚合后形成 衰老过程中的淀粉样血管病变、淀粉样斑块和神经纤维缠结， AD和唐氏症。所有90多岁的人都会发生这种情况。 遗传、毒性和感染因素可能会加速大脑老化。 淀粉样蛋白沉积。