Functional Genetics of Susceptibility to Prions

描述（由申请人提供）朊病毒疾病是 人类和动物的神经退行性疾病，包括 朊病毒蛋白（PrP）。这些疾病可以表现为遗传性、传染性或 散发性疾病和每一种类型往往是传染给实验 动物朊病毒引起的疾病包括羊瘙痒病、牛海绵状病毒病、 脑病（BSE）和克雅氏病（CJD）。所有朊病毒 疾病涉及PrP构象的变化， 同种型PrPC转化为疾病特异性同种型PrPsc。PrPsc可能是唯一的 感染性颗粒的功能成分和不同构象的 PrPsc可以加密朊病毒株的特性。起初被认为是 由外源性慢病毒引起的疾病，令人信服的证据表明， 朊病毒疾病是蛋白质构象的紊乱。的发现 多学科研究产生的新感染原理 专注于PrP该项目的四名高级研究员 申请建议将他们的合作朊病毒研究工作扩展到一个 新的方向虽然PrP是传染性的核心，但疾病易感性 和发病机制，其他分子也参与其中。最近的发现提供了 第一次有机会研究朊病毒复制和发病机制 通过关注PrP编码基因以外的基因。治疗羊瘙痒症潜伏期 时间作为一个数量性状允许识别染色体区域 携带朊病毒潜伏时间调节基因。这些基因将被识别 使用位置克隆和位置候选方法，借助于新的 DNA分析、表达微阵列和BAC工程技术， 转基因小鼠的生产。其他朊病毒修饰基因将 通过使用QTL对小鼠品系中的天然多态性进行取样来鉴定 分析和应用化学诱变筛选新型朊病毒 孵化时间基因第一个编码PrP相关蛋白Dpl的基因是 在PrP基因的下游发现。虽然PrP和DpI仅显示25% 序列同一性，它们共享保守的三螺旋束结构。这 提供了一个独特的机会，了解更多关于朊病毒复制和疾病 通过产生嵌合PrP：Dpl分子来研究PrP：Dpl的致病性。DpI错误表达 导致小脑神经变性，可通过PrP预防 表达，表明参与类似的途径，这将是 用cDNA阵列和通过鉴定修饰基因进行询问。在 除了提供朊病毒疾病的新视角，这些研究可能 最终揭示了多种CNS退行性疾病的共同途径。

DESCRIPTION (provided by applicant) Prion diseases are neurodegenerative disorders of humans and animals that involve misfolding of prion protein (PrP). These diseases can present as genetic, infectious or sporadic illnesses and each type is often transmissible to experimental animals. Diseases caused by prions include scrapie, bovine spongiform encephalopathy (BSE), and Creutzfeldt-Jakob disease (CJD) in humans. All prion diseases involve changes in the conformation of PrP from its benign cellular isoform, PrPC, to a disease-specific isoform, PrPsc. PrPsc is probably the sole functional component of the infectious particle and different conformations of PrPsc can encipher properties of prion strains. Originally thought to be diseases caused by an exogenous slow virus, convincing evidence now indicates that prion diseases are disorders of protein conformation. The discovery of a new principle of infection resulted from research involving many disciplines focused on PrP. The four senior investigators on this Program Project application propose to extend their collaborative prion research efforts in a new direction. Although PrP is central to infectivity, disease susceptibility and pathogenesis, other molecules also are involved. Recent discoveries provide the first opportunity to study mechanisms of prion replication and pathogenesis by focusing on genes other than that encoding PrP. Treating scrapie incubation time as a quantitative trait allowed the identification chromosomal regions harboring prion incubation time modifier genes. These genes will be identified using positional cloning and positional candidate approaches, aided by new technologies in DNA analysis, expression microarrays and BAC engineering for production of transgenic mice. Additional prion modifier genes will be identified by sampling natural polymorphisms in mouse strains using QTL analysis and by applying chemical mutagenesis to screen for novel prion incubation time genes. The first gene encoding a PrP-related protein, Dpl, was discovered downstream from the PrP gene. Although PrP and DpI exhibit only 25% sequence identity, they share a conserved three-helix bundle structure. This provides a unique opportunity to learn more about prion replication and disease pathogenesis through creation of chimeric PrP:Dpl molecules. DpI misexpression in brain causes cerebellar neurodegeneration that can be prevented by PrP expression, suggesting involvement of similar pathways which will be interrogated with cDNA arrays and by identification of modifier genes. In addition to providing a new perspective on prion disease, these studies may ultimately reveal pathways common to a variety of CNS degenerative disorders.