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Bioactivities of pneumococcal cell wall in neuropathogenesis

肺炎球菌细胞壁在神经发病机制中的生物活性

基本信息

批准号：
10569107
负责人：
Elaine I Tuomanen
金额：
$ 45.5万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-11-04 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10569107
关键词：
Affect Amyloid Anatomy Animal Model Architecture Area Autophagocytosis Bacteria Behavior Binding Biochemical Biology Birth Blood Circulation Brain Cell Communication Cell Cycle Kinetics Cell Death Cell Proliferation Cell Wall Cell surface Cells Cilia Circulation Data Defect Development Dimensions Drosophila genus Embryo Equilibrium Evolution Excision Exposure to FOXG1B gene Fetus Functional disorder Gram-Positive Bacterial Infections Homeostasis Human Immune Immune signaling Immunologic Receptors Individual Infection Inflammation Inflammatory Inflammatory Response Injury Innate Immune Response Link Measures Medical Meningitis Modeling Modification Molecular Morphogenesis Mus Natural Immunity Neurons Neuropathogenesis Nuclear Organ Organoids Pathogenesis Pathway interactions Pattern Placenta Pneumonia Publications Recycling Regulation Role SHH gene Sensory Sepsis Shapes Signal Induction Signal Pathway Signal Transduction Sonic Hedgehog Pathway Streptococcus pneumoniae Structure Subcellular Anatomy TLR2 gene Testing Time Work brain abnormalities cell type cognitive function experimental study fetal fly forkhead protein in utero innovation knockout animal model organism morphogens mouse model neurodevelopment neurogenesis neuroprotection novel pathogen pathogenic bacteria postnatal postnatal neuronal death pregnant programs pup receptor recycling response tissue injury trafficking transcription factor transcriptome sequencing

项目摘要

Using the pneumococcus as a model, our lab has revealed many features of the biochemical basis of the inflammatory response to bacteria in the brain. The important discovery of this application is the opening of a new area of pathogenesis at the maternal/fetal interface that will inform newly discovered cell wall/TLR2 effects as a morphogen in the brain. We have determined that cell wall, a universal pathogen associated molecular pattern, circulates in the bloodstream of pregnant mice and traverses the placenta to the fetal brain. The response of fetal neurons is not the well characterized inflammation and neuronal death of the postnatal setting but the exact opposite: neuroproliferation without inflammation. This response involves two new activities of cell wall: 1) induction of cell proliferation via TLR2 without inflammatory signaling, and 2) remodeling of embryonic brain anatomy and changes in postnatal behavior. We will further determine the relevance of these findings to the human brain using organoids. An understanding of the details of this new biology, to be investigated in this application, represents both novel bacterial pathogenesis and an avenue of high potential for tangible medical impact. Using single cell spatial RNASeq and knock out animal models, we propose to identify the signaling cascade initiated by cell wall to modulate brain structure, including determining the links between TLR2/6, the signaling node of the neuronal cilium and the neuronal transcription factor FoxG1. This will connect innate immune receptors to nuclear transcription factors for the first time and define a new activity of TLRs as morphogens. The involvement of the LANDO autophagy pathway will be characterized as a cell wall trafficking/removal pathway associated with defects in cognitive function.

以肺炎球菌为模型，我们的实验室揭示了肺炎球菌的生化基础的许多特征，大脑对细菌的炎症反应这项应用的重要发现是，在母体/胎儿界面打开一个新的发病机制领域，细胞壁/TLR 2作为脑中的形态发生素的作用。我们已经确定细胞壁，一种普遍的病原体相关的分子模式，在怀孕小鼠的血流中循环，并穿过胎盘到胎儿大脑胎儿神经元的反应不是特征性的炎症，出生后环境中的神经元死亡，但恰恰相反：无炎症的神经增殖。这种反应涉及细胞壁的两种新活性：1）通过TLR 2诱导细胞增殖，而不炎症信号，和2）胚胎脑解剖结构的重塑和出生后的变化行为我们将进一步确定这些发现与使用类器官的人脑的相关性。对这种新生物学的细节的理解，将在本申请中进行研究，既有新的细菌致病机制，又有切实的医学影响的高潜力途径。使用单细胞空间RNASeq和敲除动物模型，我们提出识别信号级联启动细胞壁调节大脑结构，包括确定TLR 2/6之间的联系，神经元纤毛的信号传导节点和神经元转录因子FoxG 1。这将连接先天性免疫受体的核转录因子的第一次，并定义了一个新的活动， TLR作为形态发生剂。LANDO自噬通路的参与将被表征为细胞与认知功能缺陷相关的壁运输/移除途径。