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Utilizing a novel liquid-killing assay to gain insight into C. elegans immunity

利用新型液体杀灭测定来深入了解秀丽隐杆线虫的免疫力

基本信息

批准号：
8311400
负责人：
Natasha Kirienko
金额：
$ 5.22万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2012-02-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8311400
关键词：
Agar Animal Model Antibiotic Resistance Antibiotic Therapy Antibiotics Antimicrobial Resistance Bacterial Infections Biochemical Biological Assay Biological Models Biology Caenorhabditis elegans Cell Culture Techniques Chemicals Data Development Drosophila genus Drosophila melanogaster Eligibility Determination Enterococcus faecalis Enterococcus faecium Future Generations Genes Genetic Genetic Epistasis Genetic Processes Genetic Screening Goals Health Human Human Development Immune Immune response Immune system Immunity Immunization Infection Invertebrates Knowledge Laboratories Liquid substance Mammalian Cell Mammals Maps Mediating Methods Microbe Molecular Biology Morbidity - disease rate National Research Service Awards Natural Immunity Nematoda Organism Outcome Pathogenesis Pathway interactions Personal Satisfaction Pharmaceutical Preparations Pseudomonas aeruginosa Reporter Resistance Role Signal Pathway Signal Transduction Societies Streptococcus pneumoniae Stress Testing Therapeutic Translating Vancomycin resistant enterococcus Vertebrates Work antimicrobial arm biological adaptation to stress chemical genetics high throughput screening immune activation insight killings microbial mortality novel pathogen prevent research study response small molecule libraries

项目摘要

DESCRIPTION (provided by applicant): The spread of antimicrobial resistance is quickly outstripping the development of novel antibiotics, suggesting a looming danger for human health and well-being. One potential means for avoiding this crisis is the identification of compounds that stimulate the innate immune system, triggering increased microbial clearance by the host. In addition, these compounds are likely to prove a more difficult target for the adaptive genetic processes of microbes, as they unbalance the host-pathogen interaction, rather than simply killing the pathogen or preventing its replication. For this application, we will utilize a simple model organism, C. elegans, which possesses several experimental advantages: amenability to genetic screens, including forward, reverse, and chemical, adaptability to biochemical assays, and an evolutionarily conserved innate immune pathway similar to those of humans. I developed and partially characterized a novel liquid infection assay with this organism and used it to carry out a high-throughput screen to identify immunostimulatory compounds. For this project, infection-alleviating compounds will be tested for their ability to activate several key immune and stress pathways using transcriptional reporters. The compounds will be used to identify novel components of C. elegans immune response pathways and the targets of selected compounds will be determined. In future work, these compounds can be further tested in a variety of invertebrate and vertebrate model organisms, potentially identifying novel targets for the development of human therapeutics. PUBLIC HEALTH RELEVANCE: The expanding threat of antimicrobial resistance is rapidly outstripping the development of novel antibiotics, leading to a burgeoning menace of untreatable bacterial infections. A novel infection assay with a small worm was used to identify compounds that enhance host survival. Drugs will be tested for immunostimulatory activity, and positive hits will be analyzed to determine their mechanisms of function and will be used to identify novel components of innate immune signaling pathways.

描述（由申请人提供）：抗菌素耐药性的传播正在迅速超过新型抗生素的开发，这表明对人类健康和福祉的威胁迫在眉睫。避免这种危机的一种潜在方法是鉴定刺激先天免疫系统的化合物，从而触发宿主增加微生物清除。此外，这些化合物可能被证明是微生物适应性遗传过程的更困难的目标，因为它们使宿主-病原体相互作用不平衡，而不是简单地杀死病原体或阻止其复制。对于这种应用，我们将利用一个简单的模式生物，C。elegans，它具有几个实验优势：对遗传筛选的顺从性，包括正向，反向和化学，对生化测定的适应性，以及与人类相似的进化保守的先天免疫途径。我开发了一种新的液体感染检测方法，并对其进行了部分表征，并用它进行了高通量筛选，以确定免疫刺激化合物。在这个项目中，将测试减轻感染的化合物使用转录报告激活几个关键免疫和应激途径的能力。这些化合物将用于鉴定C.将确定线虫免疫应答途径和所选化合物的靶点。在未来的工作中，这些化合物可以在各种无脊椎动物和脊椎动物模型生物中进一步测试，可能为人类治疗药物的开发确定新的靶点。公共卫生关系：抗菌素耐药性的威胁正在迅速扩大，超过了新型抗生素的开发，导致无法治疗的细菌感染的威胁迅速增长。一种新的感染试验与一个小蠕虫被用来确定化合物，提高主机的生存。将测试药物的免疫刺激活性，并分析阳性命中以确定其功能机制，并将用于鉴定先天免疫信号传导途径的新组分。