New therapeutics for Shiga toxin-E. coli disease.

志贺毒素-E 的新疗法。

• 批准号: 8139202
• 负责人: Fumiko Obata
• 金额: $ 80.84万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8139202
• 关键词: Address; Adenosine; Agonist; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Biotechnology; Boston; Categories; Cell Culture Techniques; Cellular Stress; Characteristics; Chemistry; Clinical; Collaborations; Communicable Diseases; Coronary; Data; Data Protection; Development; Development Plans; Disease; Dose; Drug Formulations; Effectiveness; Escherichia coli; Escherichia coli EHEC; Escherichia coli O157; Exhibits; Exposure to; Generations; Goals; Hemolytic-Uremic Syndrome; Human; Image; Immune; Immunology; Immunotherapy; In Vitro; Industry; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Intestines; Kidney; Kidney Diseases; Lead; Lipopolysaccharides; Mediating; Medical; Medical center; Modeling; Morbidity - disease rate; Mus; New England; Oryctolagus cuniculus; Pathway interactions; Pharmaceutical Chemistry; Pharmacology; Phase; Physicians; Production; Property; Purinergic P1 Receptors; Research; Scientist; Shiga Toxin; Signal Transduction Pathway; Stress; Technology; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Toxin; Treatment Efficacy; United States; United States National Institutes of Health; Universities; Validation; Virginia; Work; analog; biodefense; biological adaptation to stress; burden of illness; cell type; cytotoxicity; effective therapy; foodborne outbreak; in vivo; induced pluripotent stem cell; inhibitor/antagonist; mortality; mouse model; multidisciplinary; novel; novel therapeutics; pathogen; physical property; prevent; product development; prototype; receptor; research clinical testing; research study; response; safety study

DESCRIPTION (provided by applicant): Shiga toxin-producing E. coli O157:H7 (STEC) is an emerging bacterial pathogen responsible for foodborne outbreaks of disease in the United States resulting in significant morbidity and mortality. The potent Shiga toxins (Stx1 and Stx2) together with pro-inflammatory bacterial lipopolysaccharide (LPS) are responsible for much of the disease burden and kidney damage known as the hemolytic uremic syndrome (HUS). Currently, no specific therapies are available for treatment of this disease. The primary goal of this project is to identify and test new therapeutics for STEC-associated infection and HUS. The long-range goal is to develop new therapies for clinical use that will reduce, eliminate, or prevent STEC related disease. The current focus is on interrupting the inflammation and cellular stress that take place in the kidneys following exposure to Shiga toxins plus LPS. Our hypothesis is that the most effective therapies for HUS will be those that interrupt the dictinct actions of both Shiga toxin and LPS. Thus, specific anti-inflammatory agents such as adenosine receptor agonists will be studied in detail to protect the host from the inflammation-mediated morbidity triggered by LPS. In addition, potent inhibitors of cellular ribotoxic stress will also be examined for protection against morbidity and mortality caused by the Shiga toxins. New forms of adenosine compounds with desirable pharmacological properties will be synthesized and examined for maximum efficacy in cell cultures and in a newly developed murine model of HUS that exhibits the hallmarks of HUS in humans. The most promising of the adenosine compounds will then be produced in larger quantity to complete pre-clinical testing. In addition, newly identified agents that target the Shiga toxin-induced ribotoxic stress signal transduction pathways will be examined for protection against progression to HUS. Finally, specific combinations of adenosine receptor agonists and inhibitors of cellular stress pathways will be studied for synergistic efficacy in post-exposure therapy of Shiga toxin and LPS. This project brings together medical scientists, chemists, and physicians from leading academic research centers and biotechnology industry in an effort to make available new and effective treatments for STEC-associated disease.

性状（申请方提供）：产滋贺毒素E.大肠杆菌O157：H7（STEC）是一种新出现的细菌病原体，在美国引起食源性疾病暴发，导致显著的发病率和死亡率。强效的滋贺毒素（Stx 1和Stx 2）与促炎细菌脂多糖（LPS）一起导致了许多疾病负担和肾损伤，称为溶血性尿毒综合征（HUS）。目前，没有特定的疗法可用于治疗这种疾病。该项目的主要目标是确定和测试STEC相关感染和HUS的新疗法。长期目标是开发用于临床的新疗法，以减少、消除或预防STEC相关疾病。目前的重点是中断炎症和细胞应激发生在肾脏暴露于滋贺毒素加脂多糖。我们的假设是，对HUS最有效的疗法将是那些中断滋贺毒素和LPS的支配作用的疗法。因此，特异性抗炎剂如腺苷受体激动剂将被详细研究，以保护宿主免受LPS引发的炎症介导的疾病。此外，还将检查细胞核糖毒性应激的有效抑制剂对由滋贺毒素引起的发病率和死亡率的保护。将合成具有所需药理学性质的腺苷化合物的新形式，并在细胞培养物和新开发的HUS小鼠模型中检查其最大功效，所述小鼠模型在人类中表现出HUS的特征。最有前途的腺苷化合物将被大量生产，以完成临床前测试。此外，新鉴定的靶向滋贺毒素诱导的核糖毒性应激信号转导通路的药物将被检查以防止进展为HUS。最后，将研究腺苷受体激动剂和细胞应激途径抑制剂的特定组合在滋贺毒素和LPS的暴露后治疗中的协同功效。该项目汇集了来自领先的学术研究中心和生物技术行业的医学科学家，化学家和医生，致力于为STEC相关疾病提供新的有效治疗方法。

项目成果

Natural killer T (NKT) cells accelerate Shiga toxin type 2 (Stx2) pathology in mice.

自然杀伤 T (NKT) 细胞加速小鼠体内志贺毒素 2 型 (Stx2) 的病理变化。

• DOI: 10.3389/fmicb.2015.00262
• 发表时间: 2015
• 期刊: Frontiers in microbiology
• 影响因子: 5.2
• 作者: Obata,Fumiko;Subrahmanyam,PriyankaB;Vozenilek,AimeeE;Hippler,LaurenM;Jeffers,Tynae;Tongsuk,Methinee;Tiper,Irina;Saha,Progyaparamita;Jandhyala,DakshinaM;Kolling,GlynisL;Latinovic,Olga;Webb,TonyaJ
• 通讯作者: Webb,TonyaJ

Role of Shiga/Vero toxins in pathogenesis.

• DOI: 10.1128/microbiolspec.ehec-0005-2013
• 发表时间: 2014-06
• 期刊: Microbiology spectrum
• 影响因子: 3.7
• 作者: Obata F;Obrig T
• 通讯作者: Obrig T

Shiga toxin type-2 (Stx2) induces glutamate release via phosphoinositide 3-kinase (PI3K) pathway in murine neurons.

• DOI: 10.3389/fnmol.2015.00030
• 发表时间: 2015
• 期刊: Frontiers in molecular neuroscience
• 影响因子: 4.8
• 作者: Obata F;Hippler LM;Saha P;Jandhyala DM;Latinovic OS
• 通讯作者: Latinovic OS