Botulinum Neurotoxin Trafficking and Tissue Distribution with Mouse Body Imaging

肉毒杆菌神经毒素贩运和组织分布与小鼠身体成像

• 批准号: 8584036
• 负责人: SHUOWEI CAI
• 金额: $ 7.72万
• 依托单位: UNIVERSITY OF MASSACHUSETTS DARTMOUTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-23 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8584036
• 关键词: Acute; Address; Adverse effects; Bioterrorism; Body Image; Bontoxilysin; Botulinum Toxin Type A; Botulism; Boxing; Categories; Centers for Disease Control and Prevention (U.S.); Clostridium botulinum type C; Complex; Data; Development; Diffusion; Disease; Disease Outbreaks; Dose; Drug Delivery Systems; Drug or chemical Tissue Distribution; Dyes; Esthetics; Evaluation; Fluorescence; Food; Food Poisoning; Foundations; Gastrointestinal tract structure; Growth; Health; Human; Imagery; Imaging technology; Ingestion; Intake; Intervention; Intravenous; Label; Medical; Medicine; Movement; Mus; Myopathy; Nerve; Neuromuscular Diseases; Neurotoxins; Oral; Organ; Peptide Hydrolases; Pilot Projects; Poison; Proteins; Recombinants; Reporting; Reproduction spores; Route; Serotyping; Site; Small Animal Imaging Systems; Staging; System; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Toxin; War; botulinum; botulinum toxin type B; clinical application; design; intraperitoneal; mouse model; operation; pre-clinical; protein complex; public health relevance; trafficking; uptake; whole body imaging

DESCRIPTION (provided by applicant): Botulinum neurotoxins (BoNTs), classified as category A bioterrorism agent(s) by the Centers for Disease Control (CDC), are the most toxic substances known to mankind. At the same time BoNTs are also used as effective therapeutics against numerous neuro-muscular disorders as well as for aesthetic purposes'. In its native form, BoNTs are secreted in complex forms, consisting of the 150 kDa neurotoxin and a group of neurotoxin-associated proteins (NAPs) which protect the toxin against low pH and proteases in the GI tract. Virtually all the current therapeutic products are in the complex form. Recent growth in the use of BoNTs for clinical applications, and its black box label designation by FDA, warrants a more in depth understanding of the toxin's movement from the site of its administration to various tissues and organs. Moreover, real-time uptake and trafficking information is essential to devise adequate interventions in case of food poisoning and intentional exposure cases of bioterrorism or a WMD attack in war theater. We propose to establish disposition of BoNTs within the body of a mouse model, after administering it through various routes of entry using bio-imaging technology and a non-toxic surrogate of type A BoNT (BoNT/A). We plan to address several critical questions relevant to dose, route, and rate of trafficking; and will also examine utility of the system for assessing the distribution of the toxi in different tissues. At the end of this proposed pilot study, we expect to have established a surrogate molecule (drBoNT/A) for visualization of BoNT/A uptake, trafficking, tissue distribution, and elimination routes after administration by different routes (oral, ip, intranasal etc.). The information derived from operation of such a system will be relevant to medical intervention against botulism, potential diffusion of the toxin upon therapeutic application, and t effective use of the drBoNT/A as a potential drug delivery vehicle to nerves in different tissues.

说明(申请人提供)：肉毒杆菌神经毒素(BoNTs)，被美国疾病控制中心列为A类生物恐怖分子(S)，是人类已知的毒性最大的物质。同时，BoNTs也被用作治疗许多神经肌肉疾病的有效疗法，以及用于美学目的。在其天然形式中，BoNTs以复杂的形式分泌，由150 kDa的神经毒素和一组神经毒素相关蛋白(NAP)组成，NAP保护毒素免受低pH值和胃肠道中的蛋白酶的影响。目前几乎所有的治疗产品都是复杂的形式。近年来，BoNTs在临床上的应用越来越多，FDA对其进行了黑盒标记，这使得我们有必要更深入地了解这种毒素从给药部位到各种组织和器官的运动。此外，实时获取和贩运信息对于在食物中毒和故意暴露生物恐怖主义或在战区发动大规模杀伤性武器袭击的情况下制定适当的干预措施至关重要。我们建议建立BoNTs在小鼠模型体内的处置，在使用生物成像技术和A型BONT(BONT/A)的无毒替代物通过不同的进入途径给药后。我们计划解决与剂量、路线和贩运速率相关的几个关键问题；还将检查该系统在评估毒素在不同组织中分布的实用性。在这项拟议的初步研究结束时，我们预计已经建立了一个替代分子(drBoNT/A)，用于显示不同途径(口服、IP、鼻腔等)给药后BoNT/A的摄取、运输、组织分布和消除途径。这种系统的运行所获得的信息将与针对肉毒杆菌中毒的医学干预、治疗应用时毒素的潜在扩散以及有效地将drBoNT/A作为潜在的药物输送载体应用于不同组织的神经有关。