Functional Genetics of Susceptibility to Prions

Prion疾病描述(由申请人提供)为 人类和动物的神经退行性疾病，涉及错误折叠 蛋白(PrP)。这些疾病可表现为遗传性、传染性或 散发性疾病和每种类型通常都会传播到实验中 动物。由普恩病毒引起的疾病包括瘙痒病、牛海绵状 人类的脑病(BSE)和克雅氏病(CJD)。全普赖恩 疾病涉及PrP从其良性细胞构象的变化 异构体PrPc到疾病特异性异构体PrPsc。PrPsc可能是唯一 感染性颗粒的功能成分和不同构象的 PrPsc可以对病毒株的特性进行加密。最初被认为是 由外源性慢病毒引起的疾病，现在有令人信服的证据表明 Pron病是蛋白质构象的紊乱。发现了一种 新的感染原理是多学科研究的结果 专注于PrP。该项目的四名高级调查人员 应用程序建议将他们的协作Prion研究工作扩展到 新方向。尽管PrP是传染性的核心，但疾病易感性 而发病机制中，其他分子也参与其中。最近的发现提供了 首次有机会研究病毒的复制机制和发病机制 通过关注编码PrP以外的基因。治疗瘙痒病孵化 时间作为数量性状允许识别染色体区域 含有Prion孵化时间修饰基因。这些基因将被识别出来 使用位置克隆和位置候选方法，由新的 DNA分析、表达微阵列和BAC工程技术 转基因小鼠的生产。更多的普恩修饰基因将是 利用QTL对小鼠品系的自然多态进行鉴定 化学诱变技术在筛选新蛋白中的应用 孵化时间基因。第一个编码PrP相关蛋白DPL的基因是 在PrP基因下游发现的。尽管PrP和DPI只显示了25% 序列同源性，它们共享一个保守的三螺旋束结构。这 提供了一个独特的机会来更多地了解Pron复制和疾病 通过产生嵌合PrP：DPL分子的发病机制。DPI错误表达 可通过PrP预防的小脑神经退行性变 表达，表明参与了类似的通路，将 用cDNA阵列和修饰基因的鉴定进行询问。在……里面 除了提供了一个新的视角来看待普里恩病，这些研究还可能 最终揭示了各种中枢神经系统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.