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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

基本信息

批准号：
9905512
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
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-05 至 2021-09-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9905512
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 Gene Expression Genes 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 Metabolic dysfunction 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

项目摘要

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（由申请人提供）：代谢和先天免疫反应是对多细胞生物体的长期稳态至关重要的两个原始系统，它们已经进化到促进针对不同环境挑战的合作性、适应性反应。相反，与现代高热量饮食相关的营养过剩往往会导致代谢先天免疫相互作用的失调以及肥胖和二型糖尿病等代谢疾病的发生。因此，迫切需要描述这些反应的机械联系和协调。我们研究的目标是利用果蝇（Drosophila melanogaster）作为简单的模型系统来揭示代谢-先天免疫相互作用的起源，以增进我们对饮食介导的人类代谢失衡的了解。在本提案中，我们计划描述先天免疫转录因子 NFkB 和胰岛素反应性代谢转录因子 Foxo 之间的新型相互作用。 NFkB 转录因子是进化上保守的先天免疫调节因子，正在成为代谢和先天免疫信号通路相互作用的双向通讯和协调的关键节点。利用果蝇（一种用于研究代谢和综合生理学的重要模型生物），我们之前已经确定了 Foxo 转录功能在控制 NFkB 介导的先天免疫反应中的作用。我们现在提供进一步的证据表明，果蝇脂肪体（类似于哺乳动物脂肪组织）中饮食依赖性 NFkB 活性也可以通过 Foxo 功能的调节影响脂质稳态；建立细胞 Foxo/NFkB“稳态模块”，通过转录因子活性的相互调节来控制代谢和先天免疫反应。果蝇提供了一个宝贵的、遗传上易于处理的模型来表征该模块，因为这些信号网络从果蝇到人类都是保守的。有趣的是，果蝇脂肪体结合了营养和病原体感知器官的功能，突出了代谢状态和先天免疫功能之间的内在联系。该提案有三个具体目标： (i) 评估脂肪体特异性 NFkB 活性在脂质稳态调节中的作用； (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 相互作用在营养依赖性代谢适应调节中的作用。利用果蝇中可用的强大遗传工具，结合分子、细胞、生理和高通量饮食介导的综合方法，我们将在生物组织的多个层面上定义这种相互作用。利用果蝇来探索代谢-先天免疫相互作用的起源，对于提高发现新疾病机制和药物靶点的速度具有巨大的希望，这些机制和药物靶点旨在治疗导致肥胖和 II 型糖尿病等病理的潜在代谢失衡。