PRION DIVERSITY

瘙痒病是一种可传播的神经退行性疾病，由 被称为普恩病毒的传染性病原体。唯一的一种大分子 在瘙痒病的普恩蛋白中发现了一种异常的蛋白亚型 (PrPSc)，由宿主基因编码。PrP基因(小鼠的Prn-p) 还控制了瘙痒病的敏感性和接种的间隔时间 和疾病。尽管许多研究都未能检测到 瘙痒病特异性核酸，这些阴性结果不排除 瘙痒病病原体具有非宿主基因组的可能性。这个 据报道存在大量的瘙痒病病毒“微生物菌株” 主张使用独立于主机的信息组件。然而，一些人 以前被认为是一种核酸的Pron分离株的性质 基因组，可以解释为PrP同种异型的表观遗传效应 上一任主持人。利用PRN同源小鼠品系和 为这些研究开发的转基因小鼠，实验将确定 不同的普利子分离株的哪些特性可以归因于 PrP的一级结构。来自同基因小鼠的细胞系将是 建立的目的是提供一种系统来分析瘙痒病分离株的特性 体外培养。PrP同种异型和物种是否会阻碍 瘙痒病传播反映宿主免疫反应将通过以下方式回答 严重联合免疫缺陷(SCID)小鼠的孵化时间研究。 PrP同种异型优先转换为PrPSc解释 通过不同的小鼠品系传代时，瘙痒病分离株的特性将 通过产生同种异型特异性抗体或直接蛋白来解决 测序。不能调用PrP的主要结构来说明 瘙痒病分离株在同一近交系小鼠中的不同行为 紧张。PrPSc的免疫亲和富集及变性-复性 实验解决了普恩病毒的第二个组成部分在 确定瘙痒病分离特性。PrP基因的体细胞突变 可能是人类散发性克雅氏病的原因；靶向 神经细胞系中同源重组的突变 移植到同基因小鼠身上将检验这种可能性。 多拷贝多拷贝插入的小鼠的构建 转基因将允许确定PrP表达的影响 瘙痒病潜伏期及感染可能性的检测 通过体细胞或生殖系突变而产生的自发性瘙痒。一种理解 导致不同症状、病理、 单一蛋白家族中的易感性和病程 疾病无疑将为人类退行性疾病带来新的曙光 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.