Absorption, Metabolism and Biodistribution of Prions after Oral Ingestion

口服摄入后朊病毒的吸收、代谢和生物分布

• 批准号: 8439892
• 负责人: CLAUDIO SOTO
• 金额: $ 40.25万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8439892
• 关键词: Affect; Animal Feed; Animals; Area; Behavior; Binding; Biochemical; Biodistribution; Biological Availability; Biological Process; Blood Transfusion; Brain; Cessation of life; Chronic Wasting Disease; Clinical; Complement; Consumption; Data; Deer; Disease; Drug Kinetics; Drug or chemical Tissue Distribution; Environmental Pollution; Event; Excretory function; Gastrointestinal Process; Gastrointestinal tract structure; Goals; Hamsters; Horizontal Disease Transmission; Human; In Situ; Individual; Infection; Infectious Agent; Ingestion; Intestinal Absorption; Intestines; Knowledge; Label; Length; Life; Measures; Metabolism; Molecular; Mouse Strains; Mus; Neurodegenerative Disorders; North America; Nucleic Acids; Oral; Oral Administration; Oral cavity; Pattern; Perfusion; Peripheral; PrPSc Proteins; Prevalence; Prion Diseases; Prion Pathway; Prions; Property; Protein Isoforms; Public Health; Research; Resistance; Risk; Role; Route; Site; Soil; Staging; Stomach; Symptoms; Tail; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Wild Animals; Work; absorption; base; cervid; design; gastrointestinal; in vivo; novel; oral infection; particle; prevent; research study; therapeutic development; uptake

DESCRIPTION (provided by applicant): Prion diseases are a group of fatal neurodegenerative disorders affecting animals and humans. The central pathogenic event is the conversion of the host-encoded prion protein (PrPC) into a misfolded isoform (PrPSc). PrPSc appears to be the main or sole component of the infectious agent (termed prion) that has the surprising ability to propagate the disease in the absence of nucleic acid. Prions can infect an individual by various routes, including oral ingestion, enter into the body and remain silently replicating in various tissues for a long time before causing a devastating disease in the brain. Our working hypothesis is that several biological processes, including absorption across intestinal barrier, tissue distribution, metabolism, clearance and peripheral prion replication control the fate of PrPSc in the body and determine whether or not the initial oral infection will progress into full-blown disease. The main goal of this project is to study in a detailed and quantitative manner the initial fate of prions upon oral exposure, including the estimation of gut metabolism, intestinal absorption, excretion, whole body tissue distribution, and brain uptake. In addition, we will investigate the gastrointestinal site responsible for prion absorption and the mechanism by which PrPSc penetrates the intestinal barrier. We will also study the effect of prion strains on these parameters in various animal species, including a natural prion host in large animals (cervids). Furthermore, we will study the role of PrPC expression and the interaction of PrPSc with soil particles in its fate upon ingestion in vivo. Finally, we will investigate the dynamic distribution of prions across the entire body during the period from initia infection to the manifestation of the clinical disease. The findings generated in this study will substantially increase our understanding of the mechanism controlling the fate of prions and the pathways implicated in the transport of PrPSc from the mouth to the brain. This data will provide important information to assess the risk of prion contamination in diverse tissues. More importantly, the findings generated in this project will open novel avenues to develop therapeutic strategies aiming for example to prevent prions to be absorbed in the intestine, to decrease uptake into the brain or to increase prion metabolism and elimination. PUBLIC HEALTH RELEVANCE: Prions are the protein-only component of the infectious agent responsible for prion diseases. The main goal of this project is to study the mechanism by which prions enter and get distributed in the body after oral ingestion in various experimental (mice, hamsters and transgenic mice) and natural animal species (cervids). Our studies will aim to determine in a detailed and quantitative manner gut metabolism, intestinal absorption, excretion, whole body tissue distribution, and brain uptake of prions after oral administration. The results o our study will be helpful to understand the mechanisms of prion spreading, to assess the risk of prion contamination and to design measures to avoid further spreading of prion diseases.

描述（由申请人提供）：朊病毒疾病是一组影响动物和人类的致命神经退行性疾病。中心致病事件是宿主编码的朊病毒蛋白（PrPC）转化为错误折叠的同种异构体（PrPSc）。PrPSc似乎是感染因子（称为朊病毒）的主要或唯一成分，在缺乏核酸的情况下具有令人惊讶的传播疾病的能力。朊病毒可以通过多种途径感染个体，包括口服摄入，进入人体并在各种组织中沉默地复制很长时间，然后在大脑中引起毁灭性的疾病。我们的工作假设是，几个生物学过程，包括肠屏障吸收、组织分布、代谢、清除和外周朊病毒复制控制PrPSc在体内的命运，并决定最初的口腔感染是否会发展成全面的疾病。本项目的主要目的是详细定量地研究口服暴露后朊病毒的初始命运，包括估计肠道代谢、肠道吸收、排泄、全身组织分布和脑吸收。此外，我们将研究负责朊病毒吸收的胃肠道部位以及PrPSc穿透肠道屏障的机制。我们还将研究朊病毒菌株在不同动物物种中对这些参数的影响，包括大型动物（cervids）中的天然朊病毒宿主。此外，我们将研究PrPC表达的作用以及PrPSc与土壤颗粒的相互作用在其体内摄入后的命运。最后，我们将研究从初始感染到临床疾病表现期间朊病毒在全身的动态分布。这项研究的发现将大大增加我们对朊病毒命运的控制机制和PrPSc从口腔到大脑的运输途径的理解。这一数据将为评估不同组织中朊病毒污染的风险提供重要信息。更重要的是，该项目的发现将为开发治疗策略开辟新的途径，例如防止朊病毒在肠道被吸收，减少进入大脑的吸收或增加朊病毒的代谢和消除。