New therapeutics for Shiga toxin-E. coli disease.

志贺毒素-E 的新疗法。

基本信息

批准号：
7334547
负责人：
TOM G OBRIG
金额：
$ 80.24万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2008-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7334547
关键词：
Address Adenosine Agonist Animal Model Anti-Inflammatory Agents Anti-inflammatory Biotechnology Boston Categories Cellular Stress Characteristics Chemistry Clinical Collaborations Communicable Diseases Condition Coronary Cultured Cells 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 Range Research Safety 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 concept cytotoxicity foodborne outbreak in vivo inhibitor/antagonist mortality mouse model multidisciplinary novel novel therapeutics pathogen physical property pre-clinical prevent prototype receptor research clinical testing research study response

项目摘要

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.

描述（由申请人提供）：产生志贺毒素大肠杆菌O157：H7（STEC）是一种新兴的细菌病原体，负责美国疾病的疾病爆发，导致显着的发病率和死亡率。有效的志贺毒素（STX1和STX2）以及促炎细菌性脂多糖（LPS）负责大部分疾病负担和肾脏损害，称为溶血性尿毒症综合征（HUS）。当前，尚无特定疗法可用于治疗该疾病。该项目的主要目标是识别和测试与STEC相关感染和HUS的新治疗剂。远程目标是开发新的临床用途疗法，以减少，消除或预防与STEC相关的疾病。当前的重点是中断暴露于Shiga毒素和LPS后肾脏发生的炎症和细胞应激。我们的假设是，HUS最有效的疗法将是那些中断志贺毒素和LP的执行作用的疗法。因此，将详细研究特定的抗炎药，例如腺苷受体激动剂，以保护宿主免受LPS触发的炎症介导的发病率。此外，还将检查对细胞核糖毒性应激的有效抑制剂，以防止志贺毒素引起的发病率和死亡率。将合成具有理想药理特性的腺苷化合物的新形式，并检查在细胞培养物中的最大疗效以及在人类中具有HUS标志的HUS的新鼠模型中的最大疗效。然后，腺苷化合物的最有希望的最有希望的人数更大，以完成临床前测试。此外，将检查靶向志贺毒素诱导的核糖毒性信号转导途径的新鉴定的药物，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，以在志贺毒素和LPS暴露后治疗中的协同功效。该项目汇集了领先的学术研究中心和生物技术行业的医学科学家，化学家和医师，以便为与STEC相关疾病提供新的有效治疗方法。