Foxo/NFkB Interactions in the Regulation of Metabolic Homeostasis

Foxo/NFkB 相互作用在代谢稳态调节中的作用

• 批准号: 9269555
• 负责人: Jason S Karpac
• 金额: $ 33.41万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-05 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269555
• 关键词: Address; Adipose tissue; Affect; Animal Model; Animals; Binding; Biological; Biological Models; Calories; Carbohydrates; Cells; Communication; Complex; Coupled; Development; Diet; Diet Habits; Disease; Drosophila genus; Drosophila melanogaster; Equilibrium; Etiology; Fatty acid glycerol esters; Functional disorder; Gene Expression; Gene Targeting; Genetic; Genetic Transcription; Goals; Growth; Homeostasis; Human; Immune; Immune signaling; Infection; Innate Immune Response; Innate Immune System; Insecta; Insulin; Knowledge; Lead; Lipids; Mediating; Metabolic; Metabolic Diseases; Metabolism; Modeling; Modernization; Molecular; NFKB Signaling Pathway; Natural Immunity; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organism; Overnutrition; Pathology; Pathway interactions; Pharmacologic Substance; Physiological; Physiology; Protein Engineering; Regulation; Research; Role; Sense Organs; Signal Pathway; Signal Transduction; Starvation; System; Testing; Tissues; Transcriptional Regulation; advanced system; base; biological adaptation to stress; combat; fly; innate immune function; lipid metabolism; metabolic abnormality assessment; novel; pathogen; promoter; public health relevance; response; stressor; tool; transcription factor

 DESCRIPTION (provided by applicant): Metabolic and innate immune responses, two primitive systems critical for the long-term homeostasis of multi-cellular organisms, have evolved to promote cooperative, adaptive responses against diverse environmental challenges. Conversely, over-nutrition associated with modern high-calorie diets often leads to mis-regulation of metabolic-innate immune interactions and the development of metabolic diseases, such as obesity and type II diabetes. Thus, there is a critical need to characterize the mechanistic connection and coordination of these responses. The goal of our research is to use the fruit fly, Drosophila melanogaster, as a simple model system to uncover the origin of metabolic-innate immune interactions in order to advance our knowledge of diet-mediated metabolic imbalances in humans. In this proposal, we plan to characterize a novel interaction between the innate immune transcription factor NFkB and the insulin-responsive metabolic transcription factor Foxo. NFkB transcription factors, evolutionarily conserved regulators of innate immunity, are emerging as a critical node in the bidirectional communication and coordination of metabolic and innate immune signaling pathway interactions. Using Drosophila, an important model organism for the study of metabolism and integrative physiology, we have previously established a role for Foxo transcriptional function in the control of NFkB-mediated innate immune responses. We now provide further evidence that diet-dependent NFkB activity in the Drosophila fatbody (similar to mammalian adipose tissue) can also impact lipid homeostasis through the regulation of Foxo function; establishing a cellular Foxo/NFkB 'homeostatic module' that governs metabolic and innate immune responses through mutual regulation of transcription factor activity. Drosophila provide an invaluable, genetically tractabl model to characterize this module, as these signaling networks are conserved from flies to humans. Interestingly, the Drosophila fatbody combines functions of nutrient and pathogen sensing organs, highlighting the inherent association between metabolic state and innate immune function. There are three specific aims to this proposal: (i) To assess the role of fatbody-specific NFkB activity in the regulation of lipid homeostasis; (ii) to characterize the molecular and cellular interaction between Foxo and NFkB; and (iii) to assess the role of fatbody-specific Foxo/NFkB interactions in the regulation of nutrient- dependent metabolic adaptation. Using the powerful genetic tools available in Drosophila, coupled with integrative molecular, cellular, physiological, and high-throughput diet-mediated approaches, we will define this interaction at multiple levels of biological organization. Exploiting Drosophila to explore th origin of metabolic-innate immune interactions holds tremendous promise for an enhanced rate of uncovering both novel disease mechanisms and pharmaceutical targets aimed at treating the underlying metabolic imbalances that lead to pathologies such as obesity and type II diabetes.

 描述（由适用提供）：新陈代谢和先天免疫回报，两个对多细胞生物长期稳态至关重要的原始系统已经发展为促进合作，适应性反应，以应对不同的环境挑战。相反，与现代高热量饮食相关的过度营养通常会导致代谢性免疫反应和代谢性疾病（例如肥胖症和II型糖尿病）的发展。这是迫切需要表征这些响应的机械连接和协调。我们研究的目的是使用果蝇，果蝇Melanogaster，作为一种简单的模型系统，以揭示代谢性免疫学相互作用的起源，以促进我们对人类饮食介导的代谢失衡的了解。在此提案中，我们计划表征先天免疫学转录因子NFKB与胰岛素反应性代谢转录因子FOXO之间的新型相互作用。 NFKB转录因子（进化上构成先天免疫学的调节剂）正在成为代谢和先天免疫学信号通路相互作用的双向通信和协调中的关键节点。使用果蝇是代谢和综合生理学研究的重要模型生物体，我们以前已经在控制NFKB介导的先天性免疫调查中的FOXO转录功能中发挥了作用。现在，我们提供进一步的证据表明，依赖饮食的NFKB活性（类似于哺乳动物脂肪组织）也会通过调节FOXO功能来影响脂质稳态；通过转录因子活性相互调控，建立一个控制代谢和先天免疫复杂的细胞FOXO/NFKB“稳态模块”。果蝇提供了一个宝贵的，一般的拖拉模型来表征该模块，因为这些信号网络是从苍蝇到人的保守的。有趣的是，果蝇脂肪体组合营养和病原体感应器官的功能，突出了代谢状态与先天免疫功能之间的继承关联。该提案有三个特定的目的：（i）评估脂肪特异性NFKB活性在调节脂质稳态中的作用； （ii）表征FOXO和NFKB之间的分子和细胞相互作用； （iii）评估脂肪体特异性FOXO/NFKB相互作用在养分依赖性代谢适应中的作用。使用果蝇中可用的强大遗传工具，再加上综合分子，细胞，生理和高通量饮食介导的方法，我们将在生物组织的多个级别上定义这种相互作用。利用果蝇来探索代谢性免疫学相互作用的起源，这对发现新型疾病机制和药物靶标的增强率旨在治疗潜在的代谢失衡，从而导致肥胖和II型糖尿病等病理。