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Glutarate metabolism in Salmonella

沙门氏菌中的戊二酸代谢

基本信息

批准号：
10351526
负责人：
Sebastian E Winter
金额：
$ 8.16万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-22 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10351526
关键词：
Acute Affect Anaerobic Bacteria Animal Disease Models Bacteria Bacterial Model Biological Assay Carbon Carboxylic Acids Cell physiology Colitis Degradation Pathway Development Diarrhea Dicarboxylic Acids Energy Metabolism Ensure Environment Enzymes Gastroenteritis Genetic Glucose Glutarates Goals Growth Hypochlorite Immunocompetent In Situ In Vitro Infection Inflammation Inflammatory Inflammatory Response Intervention Intestinal Content Intestines Laboratories Medical Care Costs Metabolism Modeling Molecular Mus Nature Nitric Oxide Nitrogen Nucleic Acids Nutrient Nutritional Organism Oxides Oxygen Pathogenesis Patients Population Productivity Proteins Reaction Research Role Salmonella Salmonella enterica Salmonella typhimurium Serotyping Shapes Source Testing Tissues Toxin United States Virulence Factors Work antimicrobial bacterial genetics bacterial metabolism commensal bacteria cost diarrheal disease enteric infection enteric pathogen experimental study glutaric acid gut colonization host-microbe interactions improved inflammatory disease of the intestine metabolic abnormality assessment metabolomics microbiota mouse model mutant non-typhoidal Salmonella oxidation oxidized lipid pathogen pathogenic bacteria sugar transmission process

项目摘要

PROJECT SUMMARY Infection with the bacterial pathogen Salmonella enterica serovar Typhimurium (S. Tm) is a common cause of inflammatory diarrhea. Intriguingly, intestinal inflammation drives an expansion of the S. Tm population in the gut lumen. The molecular mechanisms that support S. Tm colonization of the intestinal tract remain incompletely understood. Our central hypothesis is that the inflamed gut constitutes a peculiar nutritional environment that enables S. Tm to outgrow obligate anaerobic commensal bacteria. In this application, we will investigate how inflammatory reactive oxygen and nitrogen species are generating a diverse array of inflammation-associated small metabolites. We hypothesize that reactive oxygen and nitrogen species oxidize sugars to smaller mono- and dicarboxylic acids such as glutarate, which serve as nutrients for S. Tm to support gut colonization. We will test key aspects of our hypothesis in mouse models of infection and in vitro. We will pursue the following specific aims: 1.) Determine whether glutarate and other carboxylic acids are generated as byproducts of RNS metabolism, and 2. Investigate S. Tm glutarate metabolism in the context of infection. This work will advance our understanding of how intestinal pathogens, such as S. Tm, adapt their carbon and energy metabolism to colonize the mammalian intestinal tract. These studies are also expected to advance our understanding of how reactive oxygen and nitrogen species participate in diversity-generating reactions that shape the metabolite landscape during gut inflammation.

项目摘要感染细菌病原体肠道沙门氏菌血清型鼠伤寒沙门氏菌（S。Tm）是炎症性腹泻的常见原因。有趣的是，肠道炎症 S.肠腔中的Tm群体。的分子机制支持S. Tm在肠道的定植仍不完全清楚。我们核心假设是发炎的肠道构成了一个特殊的营养环境使S. Tm生长超过专性厌氧微生物。在这应用，我们将研究炎症反应性氧和氮物种正在产生一系列与炎症相关的小代谢物。我们假设活性氧和氮物质将糖氧化成较小的单- 和二羧酸如戊二酸，它们是S. TM支持肠道殖民我们将在小鼠感染模型中测试我们假设的关键方面和体外。我们会致力达致以下的具体目标：（1）确定戊二酸是否和其它羧酸作为RNS代谢的副产物产生，和2. 调查S.戊二酸在感染中的代谢。这项工作将推进我们对肠道病原体，如沙门氏菌，Tm，调整它们的碳，通过能量代谢在哺乳动物的肠道中定居。这些研究也有望推进我们对活性氧和氮物质参与形成代谢物景观的多样性生成反应，肠道炎症