Molecular Genetics Of Scrapie Pathogenesis

传染性海绵状脑病(TSE)是一组罕见的神经退行性疾病，包括人类的克雅氏病(CJD)、绵羊的瘙痒病、牛海绵状脑病(BSE)和马鹿、麋鹿的慢性衰弱病(CWD)。寨卡病毒的传染性可以跨越物种障碍。疯牛病已在英国感染人类，并担心慢性萎缩性胃病在美国可能会有类似的表现，这一事实突显了了解TSE发病机制和开发有效的抗TSE疗法的重要性。TSE疾病的感染源的确切性质尚不清楚。感染的易感性可能受到正常宿主蛋白(PrP-sen)和该蛋白的异常蛋白酶K抗性形式PrP-res之间的氨基酸同源性的影响。PrP-RES的形成与传染性密切相关，PrP-RES被认为是TSE疾病的感染源。了解这种蛋白质是如何形成的，对于我们理解TSE的发病机制和设计防止其合成的治疗策略至关重要。我的研究在分子和致病水平上解决了TSE疾病的许多不同方面。我的实验室尤其专注于：1)确定TSE毒株的分子基础，2)准确定义PrP-RES形成的不同细胞室，3)开发有效的治疗性TSE制剂，4)识别在TSE感染期间发生的最早事件，以及5)研究PrP参与PrP-RES特定物种形成的区域。 在过去的一年里，我们已经开始研究细胞暴露在TSE传染性之后发生的最早事件。我们已经证明，尽管所有暴露于TSE制剂的细胞类型都能支持PrP-RES的形成，但实际上只有一些细胞能够持久地产生PrP-RES并成为慢性感染。我们还开发了新的系统来研究PrP原纤维的形成，这一过程在获得性和家族性TSE疾病中可能是重要的。最后，我们启动了活体实验，研究PrP多肽疫苗治疗TSE疾病的效果。

Transmissible spongiform encephalopathies (TSE) are a group of rare neurodegenerative diseases which include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) and chronic wasting disease (CWD) in mule deer and elk. TSE infectivity can cross species barriers. The fact that BSE has infected humans in Great Britain and concerns that CWD may act similarly in the US underscores the importance of understanding TSE pathogenesis and developing effective anti-TSE therapeutics. The precise nature of the infectious agent of the TSE diseases is unknown. Susceptibility to infection can be influenced by amino acid homology between a normal host protein (PrP-sen) and the abnormal proteinase K-resistant form of this protein, PrP-res. Formation of PrP-res is closely associated with infectivity and PrP-res has been hypothesized to be the infectious agent in the TSE diseases. An understanding of how this protein is made is critical for our understanding of TSE pathogenesis and for devising therapeutic strategies to prevent its synthesis. My studies address many different aspects of the TSE diseases at both the molecular and pathogenic level. In particular, my laboratory focuses on: 1) determining the molecular basis of TSE strains, 2) precisely defining the different cellular compartments where PrP-res formation occurs, 3) development of effective therapeutic TSE agents, 4) identifying the earliest events which occur during TSE infection, and 5) studying the regions of PrP involved in the species-specific formation of PrP-res. In the last year, we have begun to study the earliest events that occur following exposure of cells to TSE infectivity. We have demonstrated that, although all cell types exposed to TSE agents can support PrP-res formation, only some are actually capable of making PrP-res persistently and becoming chronically infected. We have also developed new systems to study PrP fibril formation, a process that may be important in acquired and familial forms of TSE disease. Finally, we have initiated in vivo experiments to study the efficacy of PrP peptide vaccine approaches to TSE disease.