Activation of human TLR4 by endotoxin binding to MD-2

内毒素与 MD-2 结合激活人 TLR4

基本信息

批准号：
7198160
负责人：
Shanta M Zimmer
金额：
$ 11.9万
依托单位：
EMORY UNIVERSITY
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：
2004-07-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7198160
关键词：
Acids Adaptor Signaling Protein Adjuvant Affect Affinity Asthma Atherosclerosis Binding CD14 gene Cell surface Cells Chronic Chronic Disease Communicable Diseases Complex Cytokine Activation Development Disease Endotoxins Engineering Epidemiology Extracellular Protein Faculty Fellowship Functional disorder Future Genetic Transcription Gram-Negative Bacteria Head Human IL8 gene Immune response Immune system Immunology In Vitro Individual Infectious Disease Immunology Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interleukin-6 Intervention Knowledge Laboratories Lead Length Ligands Link Lipid A Lipids Lymphocyte Antigen 96 Measures Mediating Medicine Mentors Microbiology Molecular Molecular Genetics Morbidity - disease rate NF-kappa B Neisseria meningitidis Numbers Oligosaccharides Paclitaxel Pathogenesis Pathway interactions Pattern recognition receptor Phosphorylation Production Proteins Rate Research Research Personnel Role Salmonella Sepsis Species Specificity Specificity Structure Therapeutic Intervention Thinking Training United States Universities Vaccines Work career chemokine cytokine design endotoxin receptor extracellular human IRAK1 protein human TLR4 protein in vivo lipooligosaccharide lipopolysaccharide-binding protein macrophage medical schools microbial monocyte mortality pathogen professor receptor research study response sugar toll-like receptor 4

项目摘要

DESCRIPTION (provided by applicant): This five-year proposal is designed to promote a career as an academic clinician investigator in the fields of immunology and infectious diseases. The candidate will complete fellowship training in infectious diseases and be appointed to the faculty of the Emory University School of Medicine, Department of Medicine, Division of Infectious Diseases. Her career development will be mentored by Dr. David S. Stephens, Distinguished Professor of Medicine, and Professor of Microbiology and Immunology, and Epidemiology, and Director Division of Infectious Diseases. This research plan will be conducted in Dr. Stephens' laboratory which has a long and successful track record in microbial pathogenesis and molecular genetics. The Toll-like receptor 4 (TLR4), together with its accessory protein MD-2, and endotoxin are responsible for initiating much of the inflammatory response in sepsis caused by meningococci and other gram-negative bacteria. Previous work in the laboratory has identified an important role for meningococcal KDO2-lipid A in activation of the TLR4/MD-2 receptor complex. The hypothesis is that MD-2 is a specific determinant of TLR4 activation and that the KDOz-lipid A endotoxin structure is critically important for direct binding to MD-2. The importance of KDO in binding to MD-2, other endotoxin structural requirements for binding to MD-2 and the activation of TLR4 will be investigated. Specific Aim 1: Determine the meningococcal KDO2-lipid A structure required for interaction with the human adaptor protein MD-2 using genetically and biochemically defined meningococcal lipooligosaccharides. Specific Aim 2: Determine the general endotoxin structure required for extracellular activation of TLR4 via the accessory protein MD-2. Significance. Understanding the role of MD-2 in TLR4 activation by endotoxin may impact therapeutic interventions that modify the inflammatory immune response. This proposal will identify the components of bacterial endotoxin which are most efficiently recognized by MD-2 and presented to TLR4. The study of other diseases (e.g. atherosclerosis, inflammatory bowel disease, and asthma) with inflammatory components which are mediated by the activation of TLR4 and MD-2 may also benefit from this work.

描述（由申请人提供）：这项为期五年的建议旨在促进免疫学和传染病领域的学术临床研究者的职业。候选人将完成传染病的奖学金培训，并被任命为传染病科埃默里大学医学院的教职员工。她的职业发展将由医学杰出教授，微生物学和免疫学和流行病学教授兼传染病局长David S. Stephens博士指导。该研究计划将在斯蒂芬斯博士的实验室中进行，该实验室在微生物发病机理和分子遗传学方面具有长期成功的记录。 Toll样受体4（TLR4）及其辅助蛋白MD-2和内毒素负责引起脑膜炎球菌和其他革兰氏阴性细菌引起的败血症的大部分炎症反应。实验室的先前工作已经确定了脑膜炎球菌KDO2-脂质A在激活TLR4/MD-2受体复合物中的重要作用。假设是MD-2是TLR4激活的特定决定因素，而KDOZ-脂质A内毒素结构对于直接结合MD-2至关重要。 KDO在与MD-2结合时的重要性，将研究其他内毒素结构要求与MD-2结合和TLR4的激活。具体目标1：使用遗传和生化定义的脑膜炎球菌脂肪含糖，确定与人衔接蛋白MD-2相互作用所需的脑膜炎球菌KDO2-脂质的结构。特定目标2：确定通过辅助蛋白MD-2细胞外激活所需的一般内毒素结构。意义。了解内毒素在TLR4激活TLR4激活中的作用可能会影响改变炎症免疫反应的治疗干预措施。该建议将确定细菌内毒素的成分，这些成分最有效地通过MD-2识别并呈现给TLR4。对其他疾病（例如动脉粥样硬化，炎症性肠病和哮喘）的研究研究，这些疾病是由TLR4和MD-2激活介导的炎症成分的研究，也可能受益于这项工作。