Elucidating molecular structure of mammalian prions

阐明哺乳动物朊病毒的分子结构

基本信息

批准号：
8369629
负责人：
Ilia V Baskakov
金额：
$ 35.99万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8369629
关键词：
Aerosols Amino Acid Sequence Amyloid Fibrils Animals Biochemical Blood Bovine Spongiform Encephalopathy Brain Chronic Communicable Diseases Deer Disease Economics Environment Equipment Europe Global Change Goals Human In Vitro Individual Infectious Agent Inherited Laboratories Lead Length Measurement Methods Molecular Molecular Conformation Molecular Structure Nature Neurodegenerative Disorders Pattern PrPSc Proteins Prion Diseases Prions Proteins Protocols documentation Recombinants Research Source Structure Surgical Instruments Techniques Testing Therapeutic Vertebral column Wasting Syndrome Water Work age related amyloid structure design effective therapy insight medical schools non-prion prion-like protein aggregate protein folding protein misfolding cyclic amplification protein structure research study solid state nuclear magnetic resonance transmission process

项目摘要

DESCRIPTION (provided by applicant): Prion protein (PrP) underlies a spectrum of diseases with no established treatment and devastating human and economic consequences. While substantial progress has been made in understanding the biochemical nature of the prion infectious agent, the lack of detailed structural information about the aggregated, disease-related forms of the prion protein (PrPSc) is a major barrier to progress in the field. In the current application, we propose to elucidate the structures of ordered, disease-related prion protein aggregates using state-of-the-art techniques including solid-state NMR methods supplemented with mass-per-length and volume-per-length measurements. The three specific aims are focused on elucidating the molecular structures of three homogeneous but conformationally distinct forms of the ordered PrP aggregates prepared in vitro using highly pure full-length recombinant PrP under well-defined conditions. They include PrPSc with a high infectivity titer and two types of PrP amyloid fibrils with limited infectivity or no detectible infectivity, respectively. When the goals of this project are accomplished, the current study will identify structural features that distinguish infectious and non- infectious states of self-propagating ordered PrP aggregates and define molecular determinants of prion infectivity. Ultimately, insight gained from this research will aid in the efforts to develop effective therapeutics for prion diseases and a better understanding of the mechanisms of prion replication. Furthermore, these studies will lay the ground work for understanding the mechanisms responsible for prion-like replication of abnormal conformation of non-prion proteins associated with other neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Prion diseases are a group of fatal age-dependent neurodegenerative diseases that can arise spontaneously or be inherited, but can also be infectious. Lack of structural information about infectious, disease-related forms of the prion protein represents the major critical barrier to progress in the field. The current project seeks t elucidate the molecular structure of disease-related forms of the prion protein and define molecular determinants of prion infectivity.

描述（由申请人提供）：朊病毒蛋白（PrP）是一系列疾病的基础，目前尚无成熟的治疗方法，并对人类和经济造成毁灭性后果。虽然在了解朊病毒传染原的生化性质方面已经取得了实质性进展，但缺乏有关朊病毒蛋白（PrPSc）的聚集的、与疾病相关的形式的详细结构信息是该领域取得进展的主要障碍。在当前的应用中，我们建议使用最先进的技术来阐明有序的、与疾病相关的朊病毒蛋白聚集体的结构，包括固态核磁共振方法，辅以单位长度质量和单位长度体积测量。这三个具体目标集中于阐明三种同质但构象不同形式的有序 PrP 聚集体的分子结构，使用高纯度全长重组 PrP 在明确的条件下体外制备。它们包括具有高感染滴度的 PrPSc 和两种类型的 PrP 淀粉样原纤维，分别具有有限的感染性或不可检测的感染性。当该项目的目标实现时，当前的研究将确定区分自繁殖有序 PrP 聚集体的感染性和非感染性状态的结构特征，并定义朊病毒感染性的分子决定因素。最终，从这项研究中获得的见解将有助于开发有效的朊病毒疾病治疗方法，并更好地了解朊病毒复制机制。此外，这些研究将为理解与其他神经退行性疾病相关的非朊病毒蛋白异常构象的朊病毒样复制机制奠定基础。公共卫生相关性：朊病毒病是一组致命的年龄依赖性神经退行性疾病，可以自发发生或遗传，但也可能具有传染性。缺乏有关传染性、疾病相关形式的朊病毒蛋白的结构信息是该领域进展的主要障碍。当前的项目旨在阐明与疾病相关的朊病毒蛋白的分子结构，并定义朊病毒感染性的分子决定因素。