DNA Minor Groove-binding Drugs and Food-borne Pathogens

DNA 小沟结合药物和食源性病原体

基本信息

批准号：
7324797
负责人：
Mark A PERRELLA
金额：
$ 40.83万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-12-15 至 2009-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7324797
关键词：
AT Rich Sequence Animals Anxiety Attention Bacteremia Binding Biochemical Biological Biological Warfare Blood Blood Pressure Candidate Disease Gene Categories Cell Adhesion Molecules Cells Complement Factor B Complex DNA DNA Minor Groove Binding DNA Probes DNA Structure Data Disease Outbreaks Disruption Distamycin E-Selectin Electrophoretic Mobility Shift Assay Endotoxemia Endotoxins Escherichia coli Exposure to Food Functional disorder Gastrointestinal tract structure Gene Expression Genes Genetic Transcription Geographic Locations Goals HMGA1 gene High Mobility Group Proteins Human In Vitro Infectious Agent Inflammation Intercellular Adhesion Molecules Interferons Intestines Investigation Laboratories Metabolic Minor Minor Groove Molecular Profiling Morbidity - disease rate Mus NF-kappa B Netropsin Nitric Oxide Synthase Nuclear Nucleoproteins Organ Organism Outcome Panic Pathogenesis Patients Pharmaceutical Preparations Play Prevention Recruitment Activity Regulation Role Salmonella Salmonella typhi Stream Technology Testing Tissues Toxin Transfection United States Vascular Cell Adhesion Molecule-1 chromatin immunoprecipitation foodborne pathogen hemodynamics improved in vivo interest mortality mouse model novel therapeutics pathogen promoter research study response salmonella toxin transcription factor vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Dispersion of biological warfare agents has the potential of causing significant morbidity and mortality, and public panic. Thus, further investigation into the treatment and prevention of the detrimental consequences of biological warfare is imperative. The focus of this proposal is food-borne pathogens, particularly category B bacterial pathogens of the Salmonella species and Escherichia coli, and their toxins. Compared with other biological infectious agents, these organisms require less expertise to handle, and by contaminating food products, they have the potential to produce disease outbreaks in large groups of people and over broad geographic regions. These organisms have the potential to spread from the gastrointestinal tract into the blood stream, resulting in bacteremia and endotoxemia, which has devastating consequences in patients. Over the past several years we have been interested in the pathophysiology of endotoxin from Salmonella typhi and Escherichia coli. In recent investigations, we have preliminary data to suggest a naturally occurring compound, distamycin A, may improve outcome in a mouse model of endotoxemia. Distamycin A is known to bind to the minor groove of DNA in AT-rich regions, and its effect occurs in part by disrupting the binding of transcription factors to DNA such as nuclear factor (NF)-kappa B and interferon regulatory factors (IRFs). Our overall hypothesis is that DNA minor groove-binding drugs will suppress the expression of genes that play a critical role in the regulation of inflammation and vascular tone during an endotoxin response, and thus provide a novel therapeutic option for toxins of food-borne pathogens. Thus, the goals of this proposal are: 1) to determine whether drugs that bind to AT-rich regions of the minor groove of DNA improve outcome in mice exposed to endotoxin of the food-borne pathogens, Salmonella typhi and Escherichia coli, 2) to identify specific genes, regulated by DNA minor groove-binding drugs, that contribute to an improved response during endotoxin exposure, and 3) to characterize the mechanisms by which DNA minor groove-binding drugs alter gene expression leading to improved outcome during endotoxin exposure.

描述（由申请人提供）：生物战剂的分散物具有引起明显的发病率和死亡率以及公众恐慌的潜力。因此，必须进一步研究生物战的治疗和预防有害后果。该提案的重点是食品传播的病原体，特别是沙门氏菌和大肠杆菌的B类细菌病原体及其毒素。与其他生物传染剂相比，这些生物需要更少的专业知识来处理，并且通过污染食品，它们有可能在大批人和广泛的地理区域中产生疾病暴发。这些生物有可能从胃肠道传播到血液，导致菌血症和内毒素血症，这在患者中产生了毁灭性的后果。在过去的几年中，我们对来自鼠伤寒沙门氏菌和大肠杆菌的内毒素的病理生理感兴趣。在最近的研究中，我们有初步的数据表明，天然存在的化合物A DistaMycin A可能会改善内型血症小鼠模型中的预后。已知大霉素A与富裕区域中DNA的次要凹槽结合，其作用部分是通过破坏转录因子与DNA的结合（例如核因子（NF）-KAPPA B和干扰素调节因子（IRF）（IRFS）的结合。我们的总体假设是，DNA小凹槽结合药物将抑制内毒素反应期间在炎症和血管张力的调节中起关键作用的基因表达，因此为食物 - 传播病原体的毒素提供了一种新颖的治疗选择。 Thus, the goals of this proposal are: 1) to determine whether drugs that bind to AT-rich regions of the minor groove of DNA improve outcome in mice exposed to endotoxin of the food-borne pathogens, Salmonella typhi and Escherichia coli, 2) to identify specific genes, regulated by DNA minor groove-binding drugs, that contribute to an improved response during endotoxin exposure, and 3) to characterize DNA小凹槽结合药物改变基因表达的机制导致内毒素暴露期间的预后改善。