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A new genetic approach for studying prions and other pathogenic protein aggregate

研究朊病毒和其他致病蛋白聚集体的新遗传学方法

基本信息

批准号：
8137722
负责人：
Ann Hochschild
金额：
$ 83.9万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2014-12-31
项目状态：
已结题

项目摘要

Abstract Prions are infectious, self-propagating protein aggregates that have been implicated in a number of devastating neurodegenerative diseases known as transmissible spongiform encephalopathies. In humans, the most common TSE, Creutzfeldt-Jakob disease, typically strikes without warning, leading to death within 1 year of diagnosis for 90% of patients. The TSEs have been attributed to a specific cellular protein (PrP) that has the potential to convert to a highly structured, ? sheet-rich aggregated form (referred to as amyloid) that is thought to be the infectious agent. With no therapies that can affect either the outcome or progress of the disease, new experimental avenues are crucial. The objective of the proposed research is to mobilize bacterial genetics as a new experimental system for studying prion behavior. Having shown that the E. coli cytoplasm can support the formation of prion-like aggregates, we propose to develop a set of transcription-based genetic assays that can detect conversion of protein domains to the prion state. Using these assays, we will conduct mutant screens to identify cellular chaperones and other factors that can affect the prion process. Because of the evolutionary conservation of chaperone proteins, such screens may uncover potential new drug targets relevant to mammalian disease. We will also use bacteria-based genetic assays to screen bacterial genomes as well as the genomes of higher organisms (including mammals) for novel prion proteins. The discovery of bacterial prions could have profound implications for human health, particularly in the context of host-pathogen interactions. Finally, we envision using bacteria-based genetic assays to screen for small molecules that can hinder conversion to and/or propagation of the prion state. While our primary focus is prion disease, the tools we aim to develop should also be applicable to the large number of non-infectious neurodegenerative diseases that are associated with the formation of amyloid aggregates.

摘要朊病毒是一种具有传染性的、自我繁殖的蛋白质聚集体，与许多疾病有关。毁灭性的神经退行性疾病，称为传染性海绵状脑病。人类的最常见的TSE，即克雅氏病，通常在没有警告的情况下发作，导致1年内死亡 90%的患者获得诊断。TSE归因于一种特定的细胞蛋白（PrP），有可能转化为高度结构化的，？一种被认为是富含片状的聚集形式（称为淀粉样蛋白），成为传染源。由于没有治疗方法可以影响疾病的结果或进展，新的实验途径至关重要。拟议研究的目标是动员细菌遗传学作为一种新的实验系统，研究朊病毒的行为证明了E.大肠杆菌细胞质可以支持朊病毒样蛋白的形成聚集体，我们建议开发一套基于转录的基因检测，可以检测转换朊病毒状态的蛋白质结构域。使用这些检测，我们将进行突变筛选，以确定细胞伴侣蛋白和其他影响朊病毒过程的因素。由于进化上的保守，伴侣蛋白，这样的屏幕可能会发现潜在的新的药物靶点相关的哺乳动物疾病。我们还将使用基于细菌的遗传分析来筛选细菌基因组以及高等植物的基因组。生物体（包括哺乳动物）的新型朊病毒蛋白。细菌朊病毒的发现对人类健康的深远影响，特别是在宿主-病原体相互作用的背景下。最后我们设想使用基于细菌的遗传分析来筛选可能阻碍转化为和/或朊病毒状态的传播。虽然我们的主要焦点是朊病毒疾病，但我们旨在开发的工具也应该适用于大量的非感染性神经退行性疾病，与淀粉样蛋白聚集体的形成有关。