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Mechanisms of prion spread and establishment of infection

朊病毒传播和感染建立的机制

基本信息

批准号：
10405453
负责人：
Jason C Bartz
金额：
$ 46.27万
依托单位：
CREIGHTON 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：
2018-06-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405453
关键词：
Amyloid Animal Model Animals Axon Axonal Transport Biological Assay Blood Brain Cardiovascular system Cells Characteristics Data Detection Disease Enteric Nervous System Epithelial Event Goals Human Infection Knowledge Label Lumbar spinal cord structure Lymphatic System Mesocricetus auratus Modeling Morphologic artifacts Motor Neurons Mucous Membrane Mus Nerve Nerve Degeneration Nervous system structure Neuraxis Neurodegenerative Disorders Neurons Oral Pathogenesis Pathway interactions Peripheral Nervous System Positioning Attribute PrP PrPC Proteins PrPSc Proteins Prion Diseases Prion Pathway Prions Red nucleus structure Research Personnel Role Route Site Soil Structure Surface Synapses System Techniques Testing Time Tissues Work Zoonoses cross-species transmission detection method detection platform detection sensitivity experience illness length innovation prion hypothesis prophylactic retrograde transport sciatic nerve trafficking uptake

项目摘要

Prion diseases are inevitably fatal infectious neurodegenerative zoonotic disorders of animals, including humans, with no known cure. Prions are comprised largely, if not entirely, of PrPSc, a misfolded form of the normal non-infectious prion protein PrPC. Although the details of how prions enter the nervous system and cause disease are not known the current model consists of prion trafficking to lymphoreticular tissues (LRS), replication/accumulation in these tissues and subsequent transport into the central nervous system (CNS). Neuroinvasion is thought to occur via sympathetic nerves that innervate LRS tissue and parasympathetic nerves that innervate the enteric nervous system in the gut wall. Recent work from our group and others has shown that prions that come into contact with mucosal surfaces spread to blood within minutes and can be detected in blood for the duration of disease. The role of this prionemia in pathogenesis, including neuroinvasion, has not been examined. We provide evidence that structures at the interface of the circulatory and nervous system can support prion replication and may be important portals of prion neuroinvasion. Overall, very little is known about the site(s) of initial establishment of infection, clearance of inoculum and whether replication of agent is required for neuroinvasion. This significant problem has been hampered by the inability to differentiate inoculum PrPSc vs. newly formed PrPSc. The long-term goal of these studies is to identify the sites of initial prion replication and to identify new routes of neuroinvasion. The objective of this application is to determine the temporal and spatial spread of inoculum PrPSc in the host following natural routes of inoculation to identify the pathways of prion spread and neuroinvasion. We hypothesize that prions rapidly spread throughout the host independent of agent replication. To accomplish this objective we have developed powerful animal systems and ultrasensitive prion detection techniques that have resulted in important findings in the initial uptake and spread of prions. Our proposed innovative approach does not require enrichment or labeling of PrPSc in trans, and avoids artifacts of altered PrPSc amyloid state and limited detection sensitivity. We have shown that PrPSc or PrPSc bound to soil crosses epithelia, drains to the lymphatic system and enters blood within minutes of oral or extranasal inoculation. We also show that once prions enter the peripheral nervous system they are retrogradely transported along defined neuroanatomical pathways. Finally, we have data indicating that a lymphoreticular system (LRS) replication-deficient prion strain is transported along known prion pathways but fails to establish disease. Using this new knowledge and techniques we determine if prionemia results in rapid widespread dissemination of prions, in the absence of prion conversion, which is followed by a tissue-specific rate of decay. The results of these aims will determine the early events in prion pathogenesis and if prion conversion is required for neuroinvasion and transynaptic spread.

朊病毒病是一种不可避免的致命性传染性神经退行性动物源性疾病，包括人类，没有已知的治疗方法。朊病毒如果不是全部，也是大部分由PrPSc组成，PrPSc是朊病毒的一种错误折叠形式。正常的非感染性朊病毒蛋白PrPC。虽然朊病毒如何进入神经系统的细节，目前的模型由朊病毒运输到淋巴网状组织（LRS）组成，在这些组织中复制/积累，随后转运到中枢神经系统（CNS）。神经侵袭被认为是通过支配LRS组织和副交感神经的交感神经发生的。肠壁中支配肠神经系统的神经。我们小组和其他人最近的工作表明朊病毒与粘膜表面接触后在几分钟内扩散到血液中，在疾病期间在血液中检测到。这种朊病毒血症在发病机制中的作用，包括神经侵入，尚未检查。我们提供的证据表明，在循环界面的结构，神经系统支持朊病毒复制，可能是朊病毒侵入神经系统的重要门户。总体而言，关于感染的初始建立、接种物的清除以及是否需要复制的代理神经侵袭。这一重大问题受到了不能区分接种物PrPSc与新形成的PrPSc。这些研究的长期目标是确定朊病毒初始复制的位点，并确定新的神经侵袭途径。的目的应用是确定接种物PrPSc在宿主中的时间和空间传播，接种途径，以确定朊病毒传播和神经侵袭的途径。我们假设朊病毒快速地在整个主机中传播，而不依赖于代理复制。为了实现这一目标，我们开发了强大的动物系统和超灵敏的朊病毒检测技术，在朊病毒的初始摄取和传播方面的重要发现。我们提出的创新方法不需要反式PrPSc的富集或标记，并避免了改变的PrPSc淀粉样蛋白状态和有限的检测灵敏度我们已经证明PrPSc或与土壤结合的PrPSc穿过上皮细胞，排出到上皮细胞，淋巴系统并在口服或鼻外接种后几分钟内进入血液。我们还表明，一旦朊病毒进入周围神经系统，它们沿着沿着限定的神经解剖学的路径逆行运输。途径。最后，我们有数据表明，淋巴网状系统（LRS）复制缺陷型朊病毒毒株沿沿着已知朊病毒途径转运，但不能致病。利用这些新知识，技术，我们确定是否朊病毒血症导致朊病毒的快速广泛传播，在缺乏朊病毒转化，随后是组织特异性衰变率。这些目标的结果将决定朊病毒发病机制的早期事件以及朊病毒转化是否是神经侵袭和跨突触传播.