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，作为食物消化的媒介，产生必需的维生素，并与 我们的免疫系统允许在我们的组织中居住。这种“交流”发生在代谢物 细菌产生的蛋白质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描述了生活在我们肠道中的许多细菌物种，并将它们与各种各样的细菌物种联系起来， 正常或病理生理状态，这些复杂的微生物群的研究不能告诉我们， 单个细菌产物改变我们的细胞功能。没有这些知识，我们就无法理解 细胞通路是靶向的，或者模拟或阻断细菌反应的治疗剂的效果 会是。 为了解决这个开放的，关键的问题，我们配对了两个遗传模型，C。elegans和E.大肠杆菌， 确定哪些细菌途径影响宿主体内的脂肪积累。C.线虫消耗细菌，但是 与哺乳动物相似，许多微生物在肠道中保持完整、驻留和增殖。使用 视觉屏幕在C. elegans，我们发现多个E.缺乏柠檬酸甲酯循环的大肠杆菌突变体， 将丙酸盐转化为丙酮酸盐或琥珀酸盐，刺激脂肪生成报告基因。这个基因固醇辅酶A 脂肪去饱和酶（SCD 1）fat-7对人类是保守的，其通过固醇反应元件结合的调节也是如此 转录因子蛋白（SREBP）家族。短链脂肪酸（SCFA）如丙酸酯已经被广泛使用。 被认为是影响宿主反应的细菌产物。引人注目的是，我们发现丙酸也诱导SCD 在人精氨酸衍生的细胞系中表达。我们将使用C。秀丽线虫决定了 丙酸到脂肪生成基因表达，测试这是否需要SREBP，沿着其他转录因子， 然后将这些研究扩展到哺乳动物细胞培养。代谢性疾病通常与两个“打击”有关： 脂肪生成和免疫功能。我们以前发现，一个保守的代谢途径，增加脂肪-7， C.线虫还能刺激先天免疫反应。因此，我们还将确定丙酸盐是否发生变化 C.免疫功能elegans和哺乳动物细胞中。使用C。elegans允许一个快速的基因解剖， 脂肪生成和免疫反应，在整个动物模型的背景下识别调节途径。 我们的下一步，在人类细胞中评估这些高置信度模型，确认与哺乳动物的相关性， 重要的是，它使我们能够在更复杂的哺乳动物环境中研究这些相互作用。