Bacterial modulators of metazoan lipogenesis

后生动物脂肪生成的细菌调节剂

• 批准号: 9376448
• 负责人: Amy Karol Walker
• 金额: $ 25.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9376448
• 关键词: Address; Affect; Animal Model; Animals; Automobile Driving; B-Lymphocytes; Bacteria; Binding Proteins; Biological Assay; Butyrates; Caenorhabditis elegans; Cell Culture Techniques; Cell Line; Cell physiology; Cells; Cellular Metabolic Process; Cholesterol; Citrates; Coenzyme A; Communication; Complex; Cultured Cells; Data; Defect; Development; Dietary Fiber; Digestion; Disease; Dissection; Escherichia coli; Family member; Fatty Acids; Fatty acid glycerol esters; Food; Gene Expression; Genes; Genetic; Genetic Models; Genetic Transcription; HMGB1 Protein; Harvest; Health; Human; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunologic Markers; Individual; Inflammation; Innate Immune Response; Intestines; Knowledge; Link; Lipids; Mammalian Cell; Mammals; Membrane; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Modeling; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Organ; Pathogenicity; Pathologic; Pathway interactions; Peripheral; Phospholipids; Physiological; Physiology; Process; Proliferating; Propionates; Protein Family; Proteolytic Processing; Pyruvate; Regulation; Regulatory Element; Regulatory Pathway; Reporter; Reporting; Response Elements; Signal Transduction; Sterols; Structure; Succinates; System; Testing; Therapeutic Effect; Tissues; Visual; Vitamin B 12; Vitamins; Volatile Fatty Acids; Walkers; desaturase; experimental study; gene synthesis; genome-wide; gut microbiota; immune function; innovation; insight; lipid biosynthesis; lipid metabolism; liver function; microbial; microbial community; microbiota; microorganism; mutant; programs; propionyl-coenzyme A; residence; response; tissue processing; transcription factor

Project Summary Bacteria live in our gut, acting as agents for food digestion, producing essential vitamins and conversing with our immune systems to permit residence in our tissues. This “communication” occurs as the metabolites produced by the bacteria interact with our cells, changing signaling responses and transcriptional mechanisms. Although current studies have profiled many bacterial species living in our gut and linked them to a wide variety of normal or pathological physiological states, these studies of complex microbiota can not tell us how the individual bacterial products change our cellular function. Without this knowledge, we can't understand which cellular pathways are targeted, or what the effects of therapeutics that mimic or block bacterial responses would be. To address this open, critical question, we have paired two genetic models, C. elegans and E. coli, to determine which bacterial pathways affected fat accumulation in the host. C. elegans consume bacteria, but many of the microorganisms remain intact, reside and proliferate in the gut, similar to mammals. Using a visual screen in C. elegans, we found that multiple E. coli mutants deficient in the methylcitrate cycle, which converts propionate to pyruvate or succinate, stimulate a lipogenic reporter. This gene, the sterol Co-A desaturase (SCD1) fat-7, is conserved to humans, as is its regulation by the sterol response element binding protein (SREBP) family of transcription factors. Short chain fatty acids (SCFAs) such as propionate have been implicated as bacterial products influencing host responses. Strikingly, we found propionate also induces SCD expression in human intestine-derived cell lines. We will use C. elegans determine the mechanisms that link propionate to lipogenic gene expression, testing if this requires SREBPs, along with other transcription factors, then expand these studies to mammalian cell culture. Metabolic disease is often linked to two “hits”: lipogenesis and immune function. We previously found that a conserved metabolic pathway increasing fat-7 in C. elegans also stimulated innate immune responses. Therefore, we will also determine if propionate changes immune function in C. elegans and in mammalian cells. Use of C. elegans allows a rapid genetic dissection of lipogenic and immune responses, identifying regulatory pathways in the context of a whole animals model. Our next steps, evaluating these high confidence models in human cells, confirms relevance to mammals and, importantly, allows us to examine these interactions in the more complex mammalian context.

项目摘要 细菌生活在我们的肠道中，充当食物消化的剂，产生必需的维生素并与 我们的免疫系统允许居住在我们的组织中。这种“交流”是代谢物的 由细菌与我们的细胞相互作用，改变信号反应和转录机制。 尽管目前的研究已经介绍了许多生活在我们肠道中的细菌，并将其与种类繁多 在正常或病理生理状态下，这些对复杂微生物群的研究无法告诉我们 各个细菌产品改变了我们的细胞功能。没有这些知识，我们将无法理解 细胞途径是靶向的，或模仿细菌反应的理论的影响 会。 为了解决这个开放的关键问题，我们将两个遗传模型分别为秀丽隐杆线虫和大肠杆菌与 确定哪些细菌途径影响宿主中的脂肪积累。秀丽隐杆线虫食用细菌，但 与哺乳动物类似，许多微生物保持完整，驻留在肠道中。使用 秀丽隐杆线虫中的视觉屏幕，我们发现多个大肠杆菌突变体在甲基甲酸酯周期中缺乏 将丙酸转化为丙酮酸或琥珀酸酯，刺激脂肪生成器。这个基因，固醇Co-A 去饱和酶（SCD1）FAT-7对人类保守，正式响应元件结合的调节也是如此 蛋白质（SREBP）转录因子家族。短链脂肪酸（SCFA），例如丙酸 以细菌产品的形式实施会影响宿主反应。令人惊讶的是，我们发现丙酸也会影响SCD 在人类肠道衍生的细胞系中的表达。我们将使用秀丽隐杆线虫确定连接的机制 丙酸脂肪生成基因表达，测试是否需要SREBP，以及其他转录因子， 然后将这些研究扩展到哺乳动物细胞培养。代谢疾病通常与两个“命中”有关： 脂肪生成和免疫学功能。我们以前发现，保守的代谢途径增加了脂肪7 秀丽隐杆线虫还刺激了先天的免疫复杂。因此，我们还将确定丙酸酯是否改变 秀丽隐杆线虫和哺乳动物细胞中的免疫功能。秀丽隐杆线虫的使用允许快速遗传解剖 在整个动物模型的背景下，脂肪生成和免疫调查会鉴定调节途径。 我们的下一步，评估了人类细胞中这些高置信度模型，证实了与哺乳动物的相关性，并确认 重要的是，允许我们在更复杂的哺乳动物环境中检查这些相互作用。