Mechanisms of prion spread

朊病毒传播机制

基本信息

批准号：
8439438
负责人：
Christina Sigurdson
金额：
$ 35.32万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8439438
关键词：
Address Affect Amino Acid Sequence Amyloid beta-Protein Animals Applications Grants Autopsy Axon Axonal Transport Biological Assay Blood Brain Brain region Cessation of life Chronic Wasting Disease Communicable Diseases Deer Deterioration Development Diagnostic Disease Disease Progression Epitopes Experimental Models Exposure to GPI Membrane Anchors Goals Human Immunotherapy In Vitro Infection Infectious Agent Invaded Lead Liquid substance Lymphoid Tissue Maps Measures Membrane Modeling Molecular Molecular Conformation Molecular Structure Mus Nerve Nervous system structure Neuraxis Neurodegenerative Disorders Neurons Pathogenesis Peptide Sequence Determination Peripheral Peripheral Nerves Polymers Population PrPSc Proteins Presynaptic Terminals Prevention Prion Diseases Prions Process Property Publishing Risk Role Science Screening procedure Site Testing Tissues Transfusion Transgenic Mice Virulent exposed human population foodborne in vivo insight neuronal cell body novel therapeutics prevent prion-based protein aggregate protein misfolding retrograde transport synuclein tau Proteins therapy development transmission process uptake

项目摘要

DESCRIPTION (provided by applicant): Prion diseases are fatal neurodegenerative disorders caused by an aggregated form of the prion protein, PrPSc. Prions are the only protein aggregates that are naturally transmitted as an infectious disease, and most recently, human to human transmission likely occurred by transfusion of prion-contaminated blood. Most cases of natural transmission occur through a peripheral exposure followed by prion spread to the CNS. Although prions are thought to spread via peripheral nerves to the CNS, the molecular mechanisms underlying neuronal transit are unclear. For this reason, a major goal of this grant application is to understand how prion aggregates spread to the CNS. We hypothesize that prions propagate by retrograde axonal transport and will address this hypothesis using in vitro and in vivo experimental models. To accomplish this goal, three aims are proposed. In the first aim, we will test the mechanism of PrPSc axonal transport using compartmentalized neuronal cultures that have a liquid separation between the axon terminals and the cell bodies. We will additionally assess the peripheral nerve transport of prion strains in vivo. In the second aim, we will measure the structural properties of the highly virulent prion strains that readily spread to he CNS. In the third aim, we will determine the role of the GPI membrane anchor of PrPC on prion spread to the brain using transgenic mice and primary neurons that express PrPC possessing or lacking the GPI anchor. We expect that these studies will provide critical missing information on the basic mechanisms of prion spread that will be essential for the development of immunotherapies and novel therapeutic strategies to prevent or arrest disease progression. PUBLIC HEALTH RELEVANCE: Prion infections are caused by misfolded proteins that invade the nervous system and ultimately lead to progressive deterioration and death. In most cases, prion infections are transmitted by foodborne contamination and are thought to spread through nerves into the brain. We propose to investigate the underlying mechanisms for how prions spread to the brain in order to develop new strategies to block prion propagation.

描述（由申请人提供）：prion病是由pr蛋白的聚集形式引起的致命神经退行性疾病。王室是唯一自然传播为一种传染病的蛋白质聚集体，最近，人类到人类传播可能是通过输血受prion污染的血液而发生的。大多数自然传播的情况通过外围暴露发生，然后将prion传播到中枢神经系统。尽管人们认为王子通过外周神经传播到中枢神经系统，但尚不清楚神经元转移的分子机制。因此，该赠款申请的主要目标是了解王室骨料如何传播到中枢神经系统。我们假设prions通过逆行轴突运输传播，并将使用体外和体内实验模型来解决这一假设。为了实现这一目标，提出了三个目标。在第一个目标中，我们将使用分隔的神经元培养物测试PRPSC轴突转运的机制，这些神经元培养物在轴突末端和细胞体之间具有液体分离。我们还将评估体内prion菌株的周围神经转运。在第二个目标中，我们将测量容易扩散到CNS的高毒物菌株的结构特性。在第三个目标中，我们将使用转基因小鼠和原发性神经元来确定PRPC的GPI膜锚在大脑上扩散到大脑的作用，这些神经元表达具有或缺乏GPI锚的PRPC。我们预计，这些研究将提供有关prion座传播基本机制的严重缺失信息，这对于预防或阻止疾病进展的新型治疗策略至关重要。公共卫生相关性：prion感染是由侵袭神经系统的错误折叠蛋白引起的，并最终导致逐渐恶化和死亡。在大多数情况下，prion感染是通过食源性污染传播的，被认为通过神经传播到大脑。我们建议研究王室如何传播到大脑的基本机制，以制定新的策略来阻止王室的传播。