MAPK-mediated defense pathways against pore-forming toxins

MAPK 介导的针对成孔毒素的防御途径

基本信息

批准号：
8462632
负责人：
RAFFI V AROIAN
金额：
$ 27.65万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8462632
关键词：
Animals Antibiotics Autophagocytosis Back Bacteria Bacterial Infections Bacterial Toxins Binding Biochemical Biological Biological Assay Caenorhabditis elegans Cell membrane Cells Cellular Stress Response Clostridium Collaborations Comparative Study Cytolysis Data Defense Mechanisms Development Disease Elements Endocytosis Enterococcus faecalis Event Genes Genetic Genetic Screening Genetic screening method Genomics Germany Goals Head Heating Heavy Metals Homologous Gene Human Hypersensitivity skin testing Hypoxia Pathway Infection Intoxication Knowledge Laboratories Lead MAPK14 gene Mammalian Cell Mammals Mediating Mediator of activation protein Membrane Membrane Protein Traffic Metabolic Metabolism Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Modeling Molecular N-terminal Nematoda Oxidative Stress Pathogenesis Pathway interactions Pharmaceutical Preparations Phosphotransferases Proteins RNA Interference Regulation Research Role Small Interfering RNA Staphylococcus aureus Streptococcus Suggestion System Testing Therapeutic Toxin Uropathogenic E. coli Vibrio cholerae Virulence Virulence Factors Work design fighting gene discovery human MAPK14 protein in vivo inhibitor/antagonist jun Oncogene keratinocyte novel therapeutics pathogen pathogenic bacteria positional cloning repaired response skills stress-activated protein kinase 1

项目摘要

DESCRIPTION (provided by applicant): The broad objective of this application is to understand how host cells defend themselves against pore-forming toxins made by pathogenic bacteria. The long term objective is to use this information for development of novel therapeutics that protects humans against bacterial infection by boosting cellular defenses against pore-forming toxins. Pore-forming toxins are the largest single group of bacterial virulence factors, comprising >25% of all protein toxins made by bacteria. They are important for the in vivo virulence of many major bacterial pathogens of humans, including Staphylococcus aureus and Streptococci. Caenorhabditis elegans has emerged as an important genetically-tractable in vivo system for studying how animal cells defend against pore-forming toxins in a manner relevant to mammals. c-JUN N-terminal Kinase (JNK) mitogen-activated protein kinase (MAPK) is a central regulator of induced cellular defenses to pore-forming toxins in C. elegans, regulating half of all PFT-induced defenses. Specific Aim I will use forward and reverse genetics, genetic and biochemical tests, quantitative intoxication assays, and expression analyses to assemble as completely as possible the C. elegans JNK PFT-induced defense pathway, heading both upstream of JNK towards initial pore-formation and downstream of JNK into regulated defense subpathways. Specific Aim II involves the use of mammalian cells treated with a medically relevant pore-forming toxin to ascertain how well C. elegans defenses are conserved in mammalian cells. Specific Aim III uses a unique and powerful set of assays developed in C. elegans to study the actual mechanisms by which the JNK PFT-induced defense pathway protects cells against PFT attack. An additional goal of Specific Aim III is to uncover new cellular mechanisms for PFT defenses.

描述（由申请人提供）：本应用的广泛目的是了解宿主细胞如何捍卫自己免受致病细菌制造的孔形成毒素。长期目标是将这些信息用于开发新型治疗剂，从而通过增强细胞防御剂免受孔形成毒素来保护人类免受细菌感染的影响。孔形成毒素是最大的单一细菌毒力因子，占细菌制造的所有蛋白质毒素的25％。它们对于许多人类的许多主要细菌病原体（包括金黄色葡萄球菌和链球菌）的体内毒力很重要。秀丽隐杆线虫已成为一种重要的遗传学体内系统，用于研究动物细胞如何以与哺乳动物相关的方式抗毛孔形成毒素。 C-JUN N末端激酶（JNK）有丝分裂原激活蛋白激酶（MAPK）是诱导细胞防御剂的中心调节剂，可在秀丽隐杆线虫中形成孔形成毒素，调节所有PFT诱导的防御剂的一半。具体目的，我将使用前进和逆转遗传学，遗传和生化测试，定量中毒测定和表达分析，以尽可能完全组装秀丽隐杆线虫JNK PFT诱导的防御途径，并向JNK的上游迈向初始孔形成和初始孔形成和初始孔形成和初始孔隙形态， JNK的下游进入受监管的国防子路口。特定的目标II涉及使用用医学相关的孔形成毒素处理的哺乳动物细胞，以确定秀丽隐杆线虫防御能力在哺乳动物细胞中的保守程度。特定的目标III使用秀丽隐杆线虫中开发的独特而强大的测定集来研究JNK PFT诱导的防御途径可保护细胞免受PFT攻击的实际机制。特定目标III的另一个目标是揭示PFT防御的新细胞机制。