PRION DIVERSITY

痒病是一种传染性神经退行性疾病， 感染性病原体叫朊病毒 唯一一种 在羊瘙痒症朊病毒中发现的是朊病毒蛋白的一种异常亚型 （PrPSc），其由宿主基因编码。 PrP基因（小鼠Prn-p） 也控制羊瘙痒病的易感性和接种间隔 和疾病 尽管许多研究都未能发现 羊瘙痒症特异性核酸，这些阴性结果并不排除 瘙痒病病原体具有不依赖宿主的基因组的可能性。 的 据报道，存在大量的：微生物菌株”的羊瘙痒症朊病毒 主张独立于主机的信息组件。 但也有 朊病毒分离物的性质，以前归因于核酸 基因组，可以解释为表观遗传效应的PrP同种异型的 前任房东 利用Prn同源小鼠品系， 为这些研究开发的转基因小鼠，实验将确定 不同朊病毒分离物的哪些特性可归因于 PrP的主要结构 来自同源小鼠的细胞系将被 建立了一个系统来分析羊瘙痒病分离物的特性， 体外 是否PrP同种异型和物种障碍的问题， 羊瘙痒病传播反映宿主免疫应答， 在SCID（严重联合免疫缺陷）小鼠中的孵育时间研究。 PrP同种异型向PrPSc的优先转化解释了 羊瘙痒病分离株在通过不同小鼠品系时的特性将 通过产生同种异型特异性抗体或通过直接蛋白质 测序 PrP的主要结构不能用于解释 同一近交系小鼠中羊瘙痒病分离株的独特行为 株 PrPSc的免疫亲和富集及变性-复性 实验研究了朊病毒的第二种成分参与 确定羊瘙痒病分离株的特性。 PrP基因体细胞突变 可能导致人类散发性克雅氏病;靶向 在神经细胞系中通过同源重组发生突变， 移植到同基因小鼠将检验这种可能性。 构建携带多拷贝的多个插入物的小鼠 转基因将允许确定PrP表达的影响， 羊瘙痒病潜伏期和检查的可能性， 通过体细胞或生殖细胞突变引起的自发性瘙痒症。 的理解 导致不同的病理学，病理学， 朊病毒单一家族的易感性和病程 疾病无疑将为退行性疾病提供新的线索， 将军

Scrapie is a transmissible neurodegenerative disease that is caused by infectious pathogens called prions. The only macromolecule that has been identified in the scrapie prion is an abnormal isoform of the prion protein (PrPSc), which is encoded by a host gene. The PrP gene (Prn-p in mice) also controls scrapie susceptibility and the interval between inoculation and illness. Although many studies have failed to detect a scrapie-specific nucleic acid, these negative results do not exclude the possibility that the scrapie agent has a host-independent genome. The reported existence of numerous :microbiological strains" of scrapie prions argues for a host-independent informational component. However, some properties of prion isolates, previously attributed to a nucleic acid genome, can be explained as an epigenetic effect of the PrP allotype of the previous host. Taking advantage of Prn congenic mouse strains and transgenic mice developed for these studies, experiments will determine which properties of distinct prion isolates can be attributed to the primary structure of PrP. Cell lines from congenic mice will be established to provide a system to analyse scrapie isolate properties in vitro. The question of whether the PrP allotype and species barriers to scrapie transmission reflect host immune responses will be answered by incubation time studies in SCID (severe combined immunodeficiency) mice. Preferential conversion of PrP allotypes to PrPSc as an explanation for scrapie isolate properties on passage through different mouse strains will be addressed by producing allotype-specific antibodies or by direct protein sequencing. The primary structure of PrP cannot be invoked to account for the distinctive behavior of scrapie isolates in the same inbred mouse strain. Immunoaffinity enrichment for PrPSc and denaturation-renaturation experiments address the involvement of a second component of prions in determining scrapie isolate properties. Somatic mutation of the PrP gene may account for sporadic Creutzfeldt-Jakob disease in humans; targeting mutations through homologous recombination in neural cell lines followed by transplantation to syngeneic mice will examine this possibility. Construction of mice which harbor several insertions of multi-copy transgenes will permit determination of the influence of PrP expression of scrapie incubation period and examination of the possibility for spontaneous scrapie through somatic or germline mutation. An understanding of the mechanisms that lead to diverse symptomology, pathology, susceptibility and disease course within the single family of prion disorders will undoubtedly shed new light on degenerative disease in general.