New therapeutics for Shiga toxin-E. coli disease.

描述（由申请人提供）：产志贺毒素的大肠杆菌O157:H7 （STEC）是一种新兴的细菌病原体，在美国引起食源性疾病暴发，导致显著的发病率和死亡率。强效志贺毒素（Stx1和Stx2）与促炎细菌脂多糖（LPS）一起造成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，尚无治疗这种疾病的特异性疗法。该项目的主要目标是确定和测试stc相关感染和溶血性尿毒综合征的新疗法。长期目标是开发用于临床的新疗法，以减少、消除或预防产志贺毒素大肠杆菌相关疾病。目前的重点是阻断在暴露于志贺毒素和LPS后发生在肾脏的炎症和细胞应激。我们的假设是，对溶血性尿毒综合征最有效的治疗方法是阻断志贺毒素和脂多糖的直接作用。因此，将详细研究特异性抗炎剂，如腺苷受体激动剂，以保护宿主免受LPS引发的炎症介导的发病率。此外，还将研究细胞核素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新形式腺苷化合物，并在细胞培养和新开发的溶血性尿毒综合征小鼠模型中检测其最大功效，该模型显示出人类溶血性尿毒综合征的特征。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，新发现的靶向志贺毒素诱导的核素毒性应激信号转导途径的药物将被检查以防止进展为溶血性尿毒综合征。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LPS暴露后治疗中的协同作用。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stc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.