Replication mechanism of human prions

人类朊病毒的复制机制

基本信息

批准号：
10330439
负责人：
WITOLD K SUREWICZ
金额：
$ 51.81万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10330439
关键词：
Amyloid Binding Biologic Characteristic Biological Assay Bovine Spongiform Encephalopathy Cattle Chronic Wasting Disease Creutzfeldt-Jakob Syndrome Data Deer Deuterium Development Disease Evolution Foundations Growth Heterogeneity Human Hydrogen Hydroxyl Radical Infectious Agent Laboratories Lead Light Link Methods Modeling Molecular Molecular Conformation Mus Mutation Nature Nerve Degeneration Neurodegenerative Disorders Pathogenesis Pathogenicity Pathology Peptide Hydrolases Phenotype Play PrP PrPSc Proteins Prion Diseases Prions Process Property Proteins Publishing Research Resistance Rodent Role Seeds Signal Transduction Structure Sucrose Symptoms Techniques Testing Time Toxic effect Transgenic Mice base conformational conversion conformer disease phenotype in vivo insight novel novel strategies novel therapeutic intervention protein aggregation protein misfolding cyclic amplification sedimentation velocity tool yeast prion

项目摘要

ABSTRACT Prions are unique, protein-only infectious agents that are responsible for a group of fatal neurodegenerative diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy in cattle and chronic wasting disease in deer and elk. Human prion diseases are especially poorly understood, largely due to their vast phenotypic heterogeneity that arises from a large spectrum of diverse human prion strains. It is generally accepted that the prion agent multiplies by binding to normal prion protein (PrPC) and converting it into a conformationally distinct pathogenic molecule (PrPSc), but the mechanism of this process remains unclear. A growing number of studies suggest a critical role in prion disease pathogenesis of small, relatively protease sensitive oligomers that appear to control two fundamental steps in the disease pathogenesis: prion replication rate and toxicity. One of the primary objectives of the proposed research is to advance molecular level understanding of the properties of oligomeric PrPSc (oPrPSc) and the mechanism by which these oligomers contribute to the pathogenic process in different phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD). The first Specific Aim is to characterize the structural organization of oPrPSc and define the role of this organization in the replication, propagation and toxicity of the most common strains of sCJD. The second Aim is to identify early critical conformational steps in the interaction between PrPC and oPrPSc, the steps that likely play a major role in triggering toxic signaling, creating human prions and controlling prion evolution. If successful, the proposed studies should not only shed new light on the pathogenic mechanism in human prion disorders, but also provide a basis for understanding the relationship between PrPSc structure and strain properties of human prions.

抽象的 prion是独特的，仅蛋白质的感染剂，负责一组致命的神经退行性诸如人类的克鲁特兹菲尔特 - 贾科布疾病，牛的海绵状脑病和牛的疾病鹿和麋鹿中的慢性浪费疾病。人类pr疾病尤其知之甚少，很大程度上是由于它们的巨大表型异质性是由各种各样的人类pr菌菌株引起的。这是普遍认为，prion剂通过与正常prion蛋白（PRPC）结合而乘以其转换进入构象上不同的致病分子（PRPSC），但该过程的机制仍然存在不清楚。越来越多的研究表明，在小型，相对较小的病毒疾病发病机理中起关键作用蛋白酶敏感的低聚物似乎控制了疾病发病机理的两个基本步骤：prion 复制率和毒性。拟议研究的主要目标之一是提高分子对寡聚PRPSC（OPRPSC）的性质的水平了解和这些机制低聚物在不同表型中造成了致病过程（SCJD）。第一个具体目的是表征OPRPSC的结构组织，并定义了这一点的作用 SCJD最常见菌株的复制，传播和毒性的组织。第二个目标是确定PRPC与OPRPSC之间相互作用的早期关键构象步骤，这可能在触发有毒信号，创造人王和控制王室演变方面发挥重要作用。如果成功的研究不仅应为人类prion的致病机制提供新的启示疾病，但也为理解PRPSC结构与应变之间的关系提供了基础人王室的特性。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chronic wasting disease (CWD) prion strains evolve via adaptive diversification of conformers in hosts expressing prion protein polymorphisms.

慢性消耗性疾病（CWD）朊病毒株通过表达朊病毒蛋白多态性的宿主中构象异构体的适应性多样化而进化。

DOI：
10.1074/jbc.ra120.012546
发表时间：
2020
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
DuqueVelásquez,Camilo;Kim,Chae;Haldiman,Tracy;Kim,Chiye;Herbst,Allen;Aiken,Judd;Safar,JiriG;McKenzie,Debbie
通讯作者：
McKenzie,Debbie

Cortical and bithalamic hypometabolism by FDG-PET/CT in a patient with sporadic fatal insomnia.

FDG-PET/CT 检测散发性致命性失眠患者的皮质和双丘脑代谢低下。

DOI：
10.1212/wnl.0000000000007240
发表时间：
2019
期刊：
Neurology
影响因子：
9.9
作者：
Haight,Taylor;Mendiola,Cecelia;Solnes,Lilja;Cohen,Mark;Safar,Jiri;Schonberger,LawrenceB;Probasco,JohnC
通讯作者：
Probasco,JohnC

Variably Protease-sensitive Prionopathy in a Middle-aged Man With Rapidly Progressive Dementia.

DOI：
10.1097/wnn.0000000000000276
发表时间：
2021-09-02
期刊：
Cognitive and behavioral neurology : official journal of the Society for Behavioral and Cognitive Neurology
影响因子：
0
作者：
Huang J;Cohen M;Safar J;Auchus AP
通讯作者：
Auchus AP