Toll-like receptor signaling in the pathogenesis and prevention of prematurity

Toll 样受体信号传导在早产发病机制和预防中的作用

基本信息

批准号：
7528461
负责人：
EMMET HIRSCH
金额：
$ 32.41万
依托单位：
NORTHSHORE UNIVERSITY HEALTHSYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-30 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7528461
关键词：
Adaptor Signaling Protein Affect Binding Birth Cell Wall Cells Cessation of life Chimeric Proteins Developed Countries Developing Countries Dissection Dose Elements Embryo Transfer Endometrium Enzymes Escherichia coli Fetal Membranes Fetus Flagellin Gene Expression Genes Genotype Gram-Positive Bacteria Immune response Immune system In Vitro Inbred Mouse Incidence Induced Labor Infection Inflammation Inflammatory Interferons Knock-out Knowledge Leukocytes Ligands Link Lipopolysaccharides Maintenance Maternal-Fetal Exchange Measures Mediator of activation protein Methods Molecular Profiling Mothers Mus Mutant Strains Mice Myelogenous Names Neonatal Numbers Organism Pathogenesis Pathway interactions Pattern Recognition Peptides Peptidoglycan Phenotype Placenta Play Predisposition Pregnancy Premature Birth Premature Labor Prematurity of fetus Prevention Proteins Public Health RNA Splicing Range Rate Receptor Activation Receptor Signaling Reporter Resistance Role Sepsis Signal Pathway Signal Transduction Signal Transduction Pathway Specificity Streptococcus Synthetic Prostaglandins TLR2 gene Testing Tissues Toll-Like Receptor 2 Toll-Like Receptor Pathway Toll-like receptors Variant Viral Whole Organism Wild Type Mouse abstracting acquired immunity beta-Galactosidase cytokine fetal human TLR3 protein in vivo microorganism migration mouse model myometrium novel pathogen prevent research study response toll-like receptor 4

项目摘要

DESCRIPTION (provided by applicant): The innate immune system recognizes pathogens via the interaction of molecular constituents of microorganisms with specialized pattern recognition molecules on host cells known as toll-like receptors (TLRs). Each of the 12 known toll-like receptors engages a different set of pathogenic markers, thereby recognizing in total a large variety of microorganisms. This engagement leads to activation and induction of inflammatory mediators via only two major intracellular pathways, known as the myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent signaling pathways. The objective of this proposal is to test the hypothesis that toll-like receptor signaling via the MyD88-dependent signal transduction pathway is an essential and modifiable mediator of pathogen-induced preterm labor. This hypothesis will be tested in a mouse model by first (Specific Aim #1) characterizing the roles of the MyD88-dependent and -independent pathways in pathogen-induced labor using peptidoglycan (a TLR-2 ligand derived from Gram positive bacterial cell walls) and group B beta-hemolytic streptococcus (GBBS, a Gram positive organism associated with preterm labor and neonatal sepsis). Mutant mice lacking either TLR-2 or MyD88 will be used to define the roles of these proteins in pathogen-induced labor. In Specific Aim #2 the capacity of a negative regulator of MyD88 (a splice variant known as MyD88s) to prevent MyD88-dependent preterm birth will be tested. A new method of delivering exogenous proteins intracellularly (TAT-fusion proteins) will be used to ferry MyD88s into the gestational compartment. Finally, in Specific Aim #3 we will take advantage of a novel observation made since the first submission of this application, namely that E. coli-induced labor has an exclusive requirement for MyD88. Dissection of the respective roles of mothers and fetuses in signaling for E. coli induced labor will be conducted using pregnancies in which maternal and fetal MyD88 genotypes differ in informative ways. PUBLIC HEALTH RELEVANCE: Preterm birth affects over 12% of all deliveries in the U.S., or approximately 480,000 babies annually, and continues to be the most important cause of neonatal illness and death in developed countries. Fifty percent or more of unexplained cases of preterm birth are related to infection. The incidence of preterm delivery continues to rise in the U.S., a fact that reflects continuing deficiencies in our knowledge of the causes and mechanisms of parturition.

描述（由申请人提供）：先天免疫系统通过微生物的分子成分与宿主细胞上称为 Toll 样受体 (TLR) 的专门模式识别分子的相互作用来识别病原体。 12 种已知的 Toll 样受体中的每一种都与一组不同的致病标记物结合，从而总共识别多种微生物。这种参与仅通过两个主要的细胞内途径（称为骨髓分化因子 88 (MyD88) 依赖性和 MyD88 独立信号途径）激活和诱导炎症介质。该提案的目的是检验这样的假设：通过 MyD88 依赖性信号转导途径的 Toll 样受体信号传导是病原体诱导的早产的重要且可修饰的介质。该假设将在小鼠模型中进行测试，首先（具体目标#1）使用肽聚糖（源自革兰氏阳性细菌细胞壁的 TLR-2 配体）表征 MyD88 依赖和独立途径在病原体诱导分娩中的作用B 组 β 溶血性链球菌（GBBS，一种与早产和新生儿败血症相关的革兰氏阳性菌）。缺乏 TLR-2 或 MyD88 的突变小鼠将被用来确定这些蛋白质在病原体诱导的分娩中的作用。在具体目标#2中，将测试MyD88负调节因子（一种称为MyD88s的剪接变体）预防MyD88依赖性早产的能力。一种在细胞内输送外源蛋白（TAT 融合蛋白）的新方法将用于将 MyD88 运送到妊娠室中。最后，在具体目标 #3 中，我们将利用自首次提交本申请以来的一项新颖观察，即大肠杆菌诱导的分娩对 MyD88 有排他性要求。将利用母体和胎儿 MyD88 基因型以信息方式不同的妊娠来剖析母亲和胎儿在大肠杆菌诱导分娩信号中各自的作用。公共卫生相关性：早产影响了美国 12% 以上的分娩，即每年约 480,000 名婴儿，并且仍然是发达国家新生儿疾病和死亡的最重要原因。百分之五十或更多的不明原因早产病例与感染有关。在美国，早产的发生率持续上升，这一事实反映出我们对分娩原因和机制的了解仍然不足。