Vaccines and therapies against botulism

肉毒杆菌中毒疫苗和疗法

• 批准号: 8448664
• 负责人: Joseph T Barbieri
• 金额: $ 77.91万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448664
• 关键词: Basic Science; Binding; Biochemical; Biochemistry; Biological; Bontoxilysin; Botulinum Toxin Type A; Botulism; Breathing; CCRL2 gene; Categories; Cells; Centers for Disease Control and Prevention (U.S.); Chicago; Clinical; Clostridial Neurotoxin; Complement; Core Facility; Cutaneous; Escherichia coli; Future; General Population; Human; Infantile Botulism; Intervention; Intoxication; Investigation; Laboratories; Modeling; Molecular; Mus; Neurons; Paralysed; Property; Proteins; Recording of previous events; Research; Research Project Grants; Role; Route; Serotyping; Serum; Solubility; Subunit Vaccines; Toxin; Translating; Translational Research; Universities; Vaccine Therapy; Vaccines; Variant; base; biodefense; botulinum toxin type B; disorder prevention; efficacy testing; foodborne; high throughput screening; inhibitor/antagonist; mouse model; neurophysiology; neurotoxin receptor; neutralizing vaccine; pathogen; receptor; receptor vaccine; research study; response; small molecule; structural biology; three dimensional structure; translational study

The botulinum neurotoxins (BoNTs) are the most toxic proteins for humans and have been classified as Category A toxins by the Centers for Disease Control and Prevention. In addition to the natural routes of intoxication (food borne botulism, cutaneous botulism, and infant botulism), inhalation botulism has been proposed as a delivery mechanism for malicious activity. Current vaccines and therapies against botulism are in limited supply for the general public. There are seven serotypes of BoNTs (termed A-G) based upon cross sero-protection. As proof of principle, a subunit vaccine was been produced that protected against intoxication by the seven serotypes of BoNT. This application will continue to develop vaccines and therapies against botulism and characterize the BoNT dual-receptors on neurons. The aims of this application are to optimize subunit BoNT vaccines that neutralize the seven serotypes of BoNT, to characterize a "new" BoNT serotype, to determine the molecular basis for the neutralization capacity of BoNT anti-sera, and to use an inhalation mouse BoNT model to test the efficacy of BoNT vaccines and determine the role of BoNT dual-receptors in inhalation botulism. A high throughput screen will identify small molecule inhibitors of BoNT entry into neurons, while the molecular and cellular properties of BoNT binding to their dual-receptors will be determined. These biochemical, biophysical, and structural studies provide a framework for translational research to develop the current and future vaccines and therapies against botulism. The research team has a history of collaborative investigations and includes expertise in the analysis of the structural biology, biochemistry, and neurophysiology of BoNT action. The GLRCE BoNT Core Facility, the University of Chicago Rickett's Regional Biocontainment Laboratory, the Argonne Structural Biology Center, and the NMR Facility at MCW will be utilized to facilitate these studies. Determining the mechanism for BoNT intoxication of neurons provides basic information that can be translated into an optimal subunit BoNT vaccine, to develop strategies to neutralize BoNT intoxication, and to expand the use of BoNT in clinical therapies. This information is also applicable for the rapid response to the intentional release of BoNT serotype variants.

肉毒杆菌神经毒素（BONTS）是人类最有毒的蛋白质，已被归类为 疾病控制与预防中心A类毒素。除了自然路线 中毒（食物传播的肉毒杆菌，皮肤肉毒杆菌和婴儿肉毒杆菌主义），吸入肉毒杆菌症已经存在 提议作为恶意活动的交付机制。当前针对肉毒杆菌的疫苗和疗法 公众的供应有限。有七种基于BONT的血清型（称为A-G） 交叉血清保护。作为原理的证明，生产了一种保护免受的亚基疫苗 Bont的七种血清型中毒。该应用程序将继续开发疫苗，并 反对肉毒杆菌的疗法并表征神经元上的双重受体。 该应用的目的是优化中和七种血清型的亚基BONT疫苗 BONT，表征“新” BONT血清型，以确定中和的分子基础 BONT抗SERA的容量，并使用吸入小鼠BONT模型测试BONT的功效 疫苗并确定双双受体在吸入肉毒杆菌中的作用。高吞吐量屏幕将 鉴定出BONT进入神经元的小分子抑制剂，而分子和细胞特性 将确定与双重受体结合的BONT。这些生化，生物物理和结构 研究为转化研究提供了一个框架，以开发当前和未来的疫苗和 反对肉毒杆菌的疗法。 研究团队有合作研究的历史，并在分析中包括专业知识 BONT作用的结构生物学，生物化学和神经生理学。 Glrce Bont核心设施， 芝加哥大学里克特大学的区域生物疗养实验室，Argonne结构生物学中心， MCW的NMR设施将用于促进这些研究。确定机制 神经元的Bott中毒提供了可以将其转化为最佳亚基BONT的基本信息 疫苗，制定策略以中和bont陶醉，并在临床上扩大BONT的使用 疗法。此信息还适用于对BONT有意释放的快速响应 血清型变体。