New therapeutics for Shiga toxin-E. coli disease.

描述(申请人提供)：产生志贺毒素的大肠杆菌O157：H7(STEC)是一种新出现的细菌病原体，可导致美国食源性疾病的暴发，导致严重的发病率和死亡率。强效志贺毒素(STX1和STX2)与促炎细菌脂多糖(LPS)一起导致了被称为溶血性尿毒症综合征(HUS)的大部分疾病负担和肾脏损害。目前，还没有治疗这种疾病的特效疗法。该项目的主要目标是确定和测试针对STEC相关感染和HUS的新疗法。长期目标是开发临床使用的新疗法，以减少、消除或预防STEC相关疾病。目前的重点是阻断接触志贺毒素加脂多糖后肾脏发生的炎症和细胞应激。我们的假设是，对HUS最有效的治疗方法将是那些同时干扰志贺毒素和脂多糖的独裁作用的治疗方法。因此，将详细研究特定的抗炎药，如腺苷受体激动剂，以保护宿主免受内毒素引发的炎症介导的发病率的影响。此外，还将研究有效的细胞核毒应激抑制剂，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新形式的腺苷化合物，并在细胞培养和新开发的HUS小鼠模型中检验其最大功效，该模型显示出人类HUS的特征。然后，最有希望的腺苷化合物将被大量生产，以完成临床前测试。此外，针对志贺毒素诱导的核毒应激信号转导通路的新发现的药物将被检查以防止进展到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志贺毒素和脂多糖暴露后治疗中的协同效果。该项目汇集了来自领先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，努力为STEC相关疾病提供新的有效治疗方法。

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.