C. elegans to study organismal control of recovery from bacterial infections

线虫研究细菌感染恢复的有机控制

基本信息

批准号：
9176010
负责人：
Alejandro Aballay
金额：
$ 39.46万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-11-05 至 2017-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9176010
关键词：
Ablation Acute American Society of Hematology Animals Antibiotic Therapy Antibiotics Autoimmune Diseases Bacterial Infections Biological C. elegans genome Caenorhabditis elegans Cells Chronic Collaborations Computer Simulation Disease Dissection Drug Metabolic Detoxication Endocrine Exhibits Failure G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Gene Expression Profiling Genes Genetic Genetic Transcription Homeostasis Immune response Immune system Immunity Infection Inflammation Inflammatory Innate Immune Response Laboratories Lead Ligands Link Mediator of activation protein Metabolism Modeling Natural Immunity Nature Nematoda Nervous System control Nervous system structure Neurons Neuropeptides Neurosecretory Systems Neurotransmitters Organism Oxidation-Reduction Pathway interactions Pharmaceutical Preparations Phase Physiological Physiological Processes Physiology Proteins Publishing Receptor Cell Recovery Recurrence Regulation Resolution Role Signal Transduction Signaling Molecule Surface Synapses System Technology Testing Tissues Universities Virulence Factors Wound Healing Xenobiotics base design dopaminergic neuron experimental study genetic approach immune activation insight killings microbial mutant neural circuit neuroregulation new therapeutic target optogenetics pathogen promoter protein folding public health relevance receptor function receptor-mediated signaling relating to nervous system response reverse genetics transcription factor

项目摘要

DESCRIPTION (provided by applicant) This proposal describes experiments designed to understand the mechanisms involved in the control of recovery from bacterial infections. To recover from an infection and return to homeostasis, the host must activate mechanisms capable of controlling the damage caused by pathogen virulence factors, inflammation, and a potentially toxic antibiotic exposure. Failure to properly recover from infections manifests in the form of recurrent infections, inappropriate wound healing, autoimmune diseases, and chronic inflammatory disorders. The mechanisms involved in pathogen recognition and immune activation have been very well studied, but the cellular and systemic responses involved in recovery after an infection is cleared are not well defined. We have established a Caenorhabditis elegans model of acute infection and antibiotic treatment for studying biological changes during the resolution phase of an infection. We found that genes that are markers of innate immunity are downregulated upon recovery, while genes involved in xenobiotic detoxification, redox regulation, and cellular homeostasis are upregulated. Using gene expression profiling, in silico analysis, and reverse genetic approaches, we have linked to the control of recovery from infection to the function of conserved transcription factors, including th GATA transcription factor ELT-2, the FOXO transcription factor DAF-16, and the Nrf transcription factor SKN-1. The proposed experiments will explore the general hypothesis that neural GPCRs and cell non-autonomous signals from different neurons may act on non-neural tissues to regulate recovery from infection at the organismal level. Given the conserved nature of GPCR-mediated signaling and the conservation of the transcription factors involved in the control of recovery, the proposed studies should lead to a better understanding of the mechanisms used by metazoans to control recovery from bacterial infection at the whole animal level.

描述（由适用提供）本提案描述了旨在了解控制细菌感染恢复的机制的实验。要从感染中恢复并恢复到体内稳态，宿主必须激活能够控制因病原体病毒因素，感染和潜在有毒抗生素暴露造成的损害的机制。未能从感染中正确恢复复发性感染，不适当的伤口愈合，自身免疫性疾病和慢性炎症性疾病的形式。病原体识别和免疫激活所涉及的机制已经很好地研究了，但是清除感染后恢复后涉及的细胞和全身反应尚未得到很好的定义。我们已经建立了一种急性感染和抗生素治疗模型，用于研究感染的分辨率阶段的生物学变化。我们发现，恢复后，是先天免疫标记的基因被下调，而涉及异生物源解毒，氧化还原调节和细胞稳态的基因被更新。使用基因表达分析，在计算机分析和反向遗传方法中，我们与控制从感染的恢复到组成转录因子的功能的控制，包括ThA转录因子ELT-2，FOXO转录因子DAF-16和NRF转录因子SKN-1。提出的实验将探讨以下一般假设：来自不同神经元的中性GPCR和细胞非自治信号可能作用于非神经组织以调节有机水平的感染中的恢复。鉴于GPCR介导的信号传导的保守性质以及控制恢复控制的转录因子的保守性，拟议的研究应更好地理解后生动物在整个动物水平上控制从细菌感染中恢复的机制。