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SHIGA-TOXINS: PRE-CLINICAL ANIMAL MODEL DEVELOPMENT AND THERAPEUTIC TESTING

志贺毒素：临床前动物模型开发和治疗测试

基本信息

批准号：
7324405
负责人：
Shinichiro Kurosawa
金额：
$ 73.26万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
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/7324405
关键词：
Agonist Animal Model Antibiotic Therapy Antibiotics Apoptosis Area Bacteria Bacterial Toxins Basic Science Binding Blood Circulation C-Peptide Canada Carbohydrates Cardiac Cattle Cells Ceramides Cessation of life Child Cities Clinical Markers Clinical Treatment Clinical Trials Colitis Communities Data Data Set Dendrimers Development Diarrhea Disease Outbreaks Dose Drug Kinetics Elderly Encephalopathies Environment Escherichia coli Escherichia coli EHEC Escherichia coli O157 Family suidae Food Foundations HIV-1 Health Sciences Hemolytic-Uremic Syndrome Household Human Infant Infection Inflammatory Infusion procedures Injury Intensive Care International Japan Kidney Laboratories Lead Link Mediator of activation protein Medical center Metabolic Modeling Mus Neurologic Organ Outcome Papio Pathogenicity Pathology Pathway interactions Peptides Pharmaceutical Preparations Physiological Physiology Protein Isoforms Protein Kinase C Public Health Rattus Renal dialysis Reperfusion Injury Research Research Personnel Resources Screening procedure Septic Toxemia Severity of illness Shiga Toxin Shiga-Like Toxin II Shiga-Like Toxins Signal Pathway Site Spinach - dietary Structure Sus scrofa System Testing Texas Therapeutic Therapeutic Intervention Thrombosis Tokyo Toxic effect Toxin Trisaccharides Universities Virulence Factors base biodefense clinically relevant college cytotoxicity design dosage glycolipid receptor holotoxins inhibitor/antagonist killings medical schools mimetics model development mortality new technology nonhuman primate novel therapeutics pre-clinical prevent programs receptor research clinical testing research study response septic synthetic peptide synthetic protein

项目摘要

DESCRIPTION (provided by applicant): Shiga-like toxin producing enterohemorrhagic Escherichia coli (EHEC) strains are recognized as the most common cause of outbreaks and regional sporadic cases of bloody diarrhea and hemolytic uremic syndrome involving thousands of cases and numerous deaths annually. These bacteria are both a public health issue and a biodefense concern due to their pervasive presence in the environment and low infective dose, and they are easily transmitted with minimal sophistication. Circulating Shiga-1 and Shiga-2 toxins (Stx1, Stx2) from the infected gut are key virulence factors of this infection, giving rise to hemorrhagic colitis, hemolytic uremic syndrome and neurological complications, particularly in infants. Clinical treatment options are limited largely to intensive support because antibiotic therapy does not appear to influence outcome or disease severity, and may actually increase toxin secretion from the bacteria. This collaborative proposal is intended to further characterize clinically relevant nonhuman primate models of Shiga toxemia and hemolytic uremic syndrome, and to use these models to investigate novel therapeutic approaches expected to prevent or counteract the pathogenicity of the EHEC Shiga-like toxins. Continued development of the nonhuman primate models of Stx1 and Stx2 toxemia will encompass definition of the physiologic, metabolic, inflammatory, and coagulopathic responses using traditional clinical markers, as well as broad-based array approaches. These models will serve as the foundation for pre-clinical testing of 1) carbohydrate-linked carbosilane dendrimers that act extracellularly as toxin receptor mimetics to neutralize toxins in the circulation and prevent cytotoxicity; and 2) conjugated synthetic protein kinase C peptides that act intracellularly to neutralize toxin-induced signaling pathways that would otherwise lead to organ injury. These studies represent a collaborative effort of five laboratories who bring their respective and unique areas of expertise to converge on pre-clinical evaluation of promising therapeutics for Shiga toxemias. There are certain strains of dangerous E. coli bacteria that can infect crops or cattle, and can be transmitted through our food distribution system to thousands of households. One recent example is contamination of spinach with the E. coli O157:H7 strain that killed two people and caused illness in hundreds in the US and Canada. These bacteria are dangerous because they secrete toxins that cause severe organ damage and we do not have drugs that will counteract these toxins. This proposal uses animal models to test new drugs that are predicted to be effective in preventing or limiting the damage done by the bacterial toxins.

描述（由申请方提供）：产生志贺样毒素的肠出血性大肠杆菌（EHEC）菌株被认为是出血性腹泻和溶血性尿毒综合征爆发和区域散发病例的最常见原因，每年涉及数千例病例和大量死亡。这些细菌既是一个公共卫生问题，也是一个生物防御问题，因为它们普遍存在于环境中，感染剂量低，而且它们很容易以最小的复杂性传播。来自感染肠道的循环滋贺-1和滋贺-2毒素（Stx 1、Stx 2）是这种感染的关键毒力因子，引起出血性结肠炎、溶血性尿毒症综合征和神经系统并发症，特别是在婴儿中。临床治疗选择主要限于强化支持，因为抗生素治疗似乎不会影响结果或疾病严重程度，实际上可能会增加细菌的毒素分泌。该合作提案旨在进一步表征滋贺毒血症和溶血性尿毒综合征的临床相关非人灵长类动物模型，并使用这些模型研究预期预防或抵消EHEC志贺样毒素致病性的新治疗方法。Stx 1和Stx 2毒血症的非人灵长类动物模型的继续开发将包括使用传统临床标记物以及广泛的阵列方法来定义生理、代谢、炎症和凝血病反应。这些模型将作为1）碳水化合物连接的碳硅烷树枝状聚合物的临床前测试的基础，其在细胞外作为毒素受体模拟物起作用，以中和循环中的毒素并防止细胞毒性;和2）缀合的合成蛋白激酶C肽，其在细胞内起作用，以中和毒素诱导的信号传导途径，否则会导致器官损伤。这些研究代表了五个实验室的合作努力，他们将各自独特的专业领域集中在滋贺毒血症有前途的治疗方法的临床前评价上。有一些危险的E.大肠杆菌可以感染农作物或牛，并可以通过我们的食品分配系统传播到成千上万的家庭。最近的一个例子是菠菜被大肠杆菌污染。大肠杆菌O 157：H7菌株，在美国和加拿大造成两人死亡，数百人患病。这些细菌是危险的，因为它们分泌毒素，导致严重的器官损伤，我们没有药物，将抵消这些毒素。该提案使用动物模型来测试预计可有效预防或限制细菌毒素造成的损害的新药。