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

• 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
• 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

 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（由申请人提供）本提案描述了旨在了解控制细菌感染恢复的机制的实验。为了从感染中恢复并恢复体内平衡，宿主必须激活能够控制病原体毒力因子、炎症和潜在毒性抗生素暴露引起的损伤的机制。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。参与病原体识别和免疫激活的机制已经得到了很好的研究，但感染清除后恢复所涉及的细胞和全身反应还没有得到很好的定义。我们建立了秀丽隐杆线虫急性感染和抗生素治疗模型，用于研究感染消退期的生物学变化。我们发现，先天免疫的标志基因在恢复后下调，而参与异生物质解毒，氧化还原调节和细胞内稳态的基因上调。利用基因表达谱分析、计算机模拟分析和反向遗传学方法，我们已经将感染后恢复的控制与保守转录因子的功能联系起来，这些转录因子包括th加塔转录因子ELT-2、FOXO转录因子EAT-16和Nrf转录因子SKN-1。拟议的实验将探索一般假设，即来自不同神经元的神经GPCR和细胞非自主信号可能作用于非神经组织，以在生物体水平上调节感染的恢复。考虑到GPCR介导的信号转导的保守性和参与恢复控制的转录因子的保守性，拟议的研究应能更好地理解后生动物在整个动物水平上控制细菌感染恢复的机制。