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：
7900346
负责人：
EMMET HIRSCH
金额：
$ 31.82万
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/7900346
关键词：
Adaptor Signaling Protein Affect Binding Birth Cell Wall Cells Cessation of life Chimeric Proteins Developed 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 Inflammation Mediators 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 Organism Pathogenesis Pathway interactions Pattern Recognition Peptides Peptidoglycan Phenotype Placenta Play Predisposition Pregnancy Premature Birth Premature Labor Prevention Proteins RNA Splicing Receptor Activation Receptor Signaling Reporter Resistance Role 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 neonatal sepsis novel pathogen premature prevent public health relevance 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被称为Toll样受体（TLR）的宿主细胞上的专门模式识别分子的相互作用识别病原体。 12个已知的Toll样受体中的每一个都具有不同的致病标记，从而识别出多种微生物。这种参与度导致仅通过两种主要细胞内途径（称为髓样分化因子88（MYD88）依赖性和MyD88独立的信号传导途径）激活和诱导炎症介质。该提案的目的是检验以下假设：通过MYD88依赖性信号转导途径Toll样受体信号传导是病原体诱导的早产劳动的必不可少且可修改的介体。该假设将在鼠标模型中通过（特定目的＃1）在鼠标模型中进行测试，以表征MyD88依赖性和与 - 独立的途径在病原体诱导的劳动中使用肽聚糖（TLR-2配体）（TLR-2配体）（从GRAM-2结合物中）与Bβ-溶血性细胞链球链球菌的阳性细胞壁和preteptoccus的prienters sepsism（GBBS）（gbbbs and a gram and a gram and n gram and n gram and n gram and n gram and n gram and n gram and n gram and n gram and n gram and）。缺乏TLR-2或MYD88的突变小鼠将用于定义这些蛋白质在病原体诱导的劳动中的作用。在特定的目标＃2中，将测试MyD88的负调节器（一种称为MyD88s的剪接变体）防止MyD88依赖性早产的能力。一种新的细胞内外源蛋白（TAT融合蛋白）输送外源蛋白的方法将用于将MyD88渡入妊娠区室。最后，在特定的目标＃3中，我们将利用自本申请第一次提交以来进行的新颖观察，即Coli诱导的劳动对MYD88具有独家要求。将使用孕妇和胎儿MyD88基因型在信息范围的方式上不同的怀孕进行解剖。公共卫生相关性：早产会影响美国所有分娩的12％以上，或每年约有480,000名婴儿，并且继续是发达国家新生儿疾病和死亡的最重要原因。 50％或以上无法解释的早产病病例与感染有关。在美国，早产的发生率不断上升，这一事实反映了我们对分娩的原因和机制的持续缺陷。