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Peptidoglycan metabolism and fragment release

肽聚糖代谢和片段释放

基本信息

批准号：
10295760
负责人：
Joseph P Dillard
金额：
$ 55.53万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10295760
关键词：
Adhesions Affect Agonist Amino Acids Bacteria Biochemical Bordetella pertussis Carboxypeptidase Cause of Death Cell Death Cell Separation Cell Wall Cells Characteristics Cicatrix Cytoplasm Cytotoxin Disaccharides Enzymes Epithelial Cells Generations Genes Glycosides Gonorrhea Gram-Negative Bacteria Growth Human IL8 gene Immune response Infection Inflammation Inflammatory Inflammatory Response Inflammatory Response Pathway Link Location Lytic Mammalian Oviducts Metabolism Methods Modeling Modification Molecular Muramidase Mutation Neisseria Neisseria gonorrhoeae Neisseria meningitidis Organism Pathogenicity Patients Pattern recognition receptor Pelvic Inflammatory Disease Peptides Peptidoglycan Process Production Proteins Proteomics Recycling Role System Tissues Trachea Virulence Factors Work cell injury cell type chronic pelvic pain cytokine dimer egg human tissue mutant neutrophil peptidoglycan monomer peptidoglycan receptor periplasm permease response transcriptomics tubal infertility uptake

项目摘要

As bacteria grow and divide, they constantly break down peptidoglycan strands to allow for cell wall expansion or reshaping the cell wall for septation and cell separation. Unlike most Gram-negative bacteria, Neisseria gonorrhoeae releases significant amounts of the peptidoglycan fragments produced during these processes. The released peptidoglycan fragments induce inflammatory responses in multiple cell types and cause sloughing of ciliated cells in the Fallopian tube. The ciliated cell sloughing is characteristic of gonococcal pelvic inflammatory disease and leads to the loss of the ability to move an egg down the oviduct. We have worked to characterize the enzymes that act in peptidoglycan breakdown so that we can understand the process of peptidoglycan fragment production. We are characterizing these enzymes to determine their substrates and products as well as subcellular localization and location relative to the septum on the gonococcal cell. Using mutants lacking genes for certain peptidoglycan degradation enzymes, we determined that ciliated cell sloughing occurs in response to peptidoglycan monomers with a three amino acid peptide, implicating pattern-recognition receptor NOD1 in the cellular response. We also discovered that gonococci release a second immunostimulatory muropeptide, a glycosidically-linked peptidoglycan dimer that stimulates NOD2. In this study we will characterize lytic transglycosylases for the generation of the peptidoglycan dimers and characterize the enzymes that create the free peptide that serves as a NOD1 agonist. We will examine AmpG function in peptidoglycan fragment recycling and determine how gonococci sense peptidoglycan fragments in the cytoplasm and regulate peptidoglycan fragment release or uptake. Finally we will characterize cellular responses to released peptidoglycan fragments to understand how Fallopian tube tissue is damaged in pelvic inflammatory disease and how neutrophils respond to released eptidoglycan fragments.

随着细菌的生长和分裂，它们不断地分解肽聚糖链以允许细胞壁扩张或重塑细胞壁以进行分隔和细胞分离。与大多数革兰氏阴性菌不同，淋病奈瑟菌在这些过程中释放大量的肽聚糖片段。释放的肽聚糖片段在多种细胞类型中诱导炎症反应，并导致输卵管中纤毛细胞脱落。纤毛细胞脱落是淋球菌性盆腔炎的特征，并导致卵子沿输卵管移动的能力丧失。我们一直致力于表征在肽聚糖分解中起作用的酶，以便我们能够理解肽聚糖片段产生的过程。我们正在表征这些酶，以确定它们的底物和产物，以及亚细胞定位和相对于淋球菌细胞隔膜的位置。使用缺乏某些肽聚糖降解酶基因的突变体，我们确定纤毛细胞脱落发生在对具有三个氨基酸肽的肽聚糖单体的响应中，这暗示了细胞应答中的模式识别受体NOD 1。我们还发现淋球菌释放第二种免疫刺激性胞肽，一种糖苷键连接的肽聚糖二聚体，刺激NOD2。在这项研究中，我们将表征裂解转糖基酶的肽聚糖二聚体的产生和表征的酶，创建作为NOD1激动剂的游离肽。我们将研究AmpG在肽聚糖片段回收中的功能，并确定淋球菌如何在细胞质中感知肽聚糖片段并调节肽聚糖片段的释放或摄取。最后，我们将描述细胞对释放的肽聚糖片段的反应，以了解输卵管组织在盆腔炎中是如何受损的，以及中性粒细胞对释放的肽聚糖片段的反应。