Structural diversity of cervid prions and phenotypic variation of chronic wasting disease

鹿朊病毒的结构多样性和慢性消耗性疾病的表型变异

• 批准号: 10657957
• 负责人: WITOLD K SUREWICZ
• 金额: $ 40.25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657957
• 关键词: Address; American; Amides; Animals; Asian; Biochemical; Biological Assay; Biological Models; Biology; Brain; Brain Diseases; Cell Culture Techniques; Characteristics; Chronic Wasting Disease; Complex; Country; Cryoelectron Microscopy; Deer; Deuterium; Disease; Epidemic; European; Family; Foundations; Future; Gene Targeting; Glutamates; Glutamine; Goals; Heritability; Heterozygote; Histidine; Human; Hydrogen; Hydroxyl Radical; In Vitro; Infectious Agent; Knowledge; Laboratories; Lead; Maintenance; Mass Spectrum Analysis; Methods; Molecular; Molecular Conformation; Mus; Neurodegenerative Disorders; Nucleic Acids; Pathogenicity; Peripheral; Phenotype; Physiological; PrP; PrPSc Proteins; Printing; Prion Diseases; Prions; Process; Property; Proteins; Public Health; Reindeer; Research; Resolution; Resources; Risk; Rodent; Route; Scandinavian; Structure; Study models; Susceptibility Gene; Testing; Variant; Vertebral column; Zoonoses; cervid; conformational conversion; cross-species transmission; foot; in vivo; insight; member; mouse model; novel; pathogen; pharmacologic; protein aggregation; structural biology; therapeutic development; tool; transmission process

Prions are the causative agents of a group of transmissible degenerative brain diseases that are fatal to humans and animals. The properties of the infectious agent and its mechanism of replication are unique. Prions are comprised of PrPSc, an abnormally folded, aggregated version of its host-encoded counterpart protein (PrPC); PrPSc self-replicates in the absence of informational nucleic acids by imposing its infectious conformation on PrPC. Our poor understanding of the structural properties of PrPSc represents an important knowledge gap in prion biology. This information is critical to elucidate the detailed mechanism of prion replication, the molecular basis of prion strain variation, and the factors controlling prion transmission between species. In this project, we focus on ascertaining the structural properties of prions causing chronic wasting disease (CWD), an uncontrollable, contagious epidemic of North American deer, elk, and other members of the cervid family, which is also emergent in Asian and European countries. The significant zoonotic potential and emergence of novel strains have established CWD as a significant public health concern. The specific objectives of our research are therefore (i) To determine structural properties of North American elk and deer CWD prions; (ii) To determine the effects of primary structural variation at prion protein residue 226 and route of transmission on CWD prion strain properties; and (iii) To determine the structural basis of strain variation in emerging Scandinavian CWD strains and an adapted derivative. Our proposed studies are truly interdisciplinary since they combine the complementary resources of two laboratories with expertise in novel mouse models for studying CWD, cell culture approaches, biochemical assays, and a host of state-of-the-art methods of structural biology. The later include several complementary mass spectrometry-based structural methods and cryo-electron microscopy, an emerging approach with high potential for providing long-sought insights into high-resolution structures of different prion strains.

朊病毒是一组对人类具有致命性的可传播的变性脑疾病的病原体 和动物感染因子的特性及其复制机制是独特的。朊病毒是 由PrPSc组成，PrPSc是其宿主编码的对应蛋白（PrPC）的异常折叠、聚集形式; PrPSc在缺乏信息核酸的情况下通过将其感染性构象强加于 PrPC。我们对PrPSc的结构性质的理解不足代表了一个重要的知识缺口， 朊病毒生物学这些信息对于阐明朊病毒复制的详细机制，即朊病毒复制的分子机制， 朊病毒株变异的基础，以及控制朊病毒在物种间传播的因素。本课题 重点是确定引起慢性消耗性疾病（CWD）的朊病毒的结构特性， 北美鹿、麋鹿和鹿科其他成员的一种无法控制的传染性流行病， 在亚洲和欧洲国家也很流行。小说的重要的人畜共患病潜力和出现 菌株已将CWD确立为重大的公共卫生问题。我们研究的具体目标是 因此（i）确定北美麋鹿和鹿CWD朊病毒的结构特性;（ii）确定 朊蛋白226位一级结构变异及传播途径对慢性消耗病朊蛋白的影响 菌株特性;以及（iii）确定斯堪的纳维亚CWD菌株变异的结构基础 菌株和适应的衍生物。我们提出的研究是真正的跨学科，因为他们结合了联合收割机， 两个实验室的互补资源，在研究慢性消耗病的新型小鼠模型，细胞 培养方法、生物化学测定和许多最先进的结构生物学方法。后期 包括几种互补基于质谱的结构方法和低温电子显微镜， 新兴的方法，具有很大的潜力，可为高分辨率结构提供长期寻求的见解， 不同的朊病毒株