Foxo/NFkB Interactions in the Regulation of Metabolic Homeostasis

 描述(申请人提供)：代谢和先天免疫反应是两个原始系统，对多细胞生物体的长期动态平衡至关重要，它们已经进化，以促进针对不同环境挑战的合作和适应性反应。相反，与现代高卡路里饮食相关的过度营养往往会导致代谢-天然免疫相互作用的错误调节，并导致代谢性疾病的发展，如肥胖症和II型糖尿病。因此，迫切需要确定这些反应的机械性联系和协调。我们的研究目标是利用果蝇作为一个简单的模型系统来揭示代谢-天然免疫相互作用的起源，以促进我们对饮食介导的人类代谢失衡的了解。在这项提议中，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之间的一种新的相互作用。NFkB转录因子是进化上保守的天然免疫调节因子，在代谢和天然免疫信号通路相互作用的双向沟通和协调中发挥着重要作用。利用果蝇这一研究新陈代谢和综合生理学的重要模式生物，我们已经确定了FOXO转录功能在调控NFkB介导的天然免疫反应中的作用。我们现在提供了进一步的证据，证明果蝇脂肪体中依赖饮食的NFkB活性(类似于哺乳动物脂肪组织)也可以通过调节FOXO功能来影响脂质稳态；建立一个细胞FOXO/NFkB‘稳态模块’，通过相互调节转录因子的活性来调控代谢和先天免疫反应。果蝇提供了一个无价的、基因上可追踪的模型来描述这个模块，因为这些信号网络从苍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。这一建议有三个具体目的：(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；以及(Iii)评估脂肪特异性FOXO/NFkB相互作用在调节营养依赖型代谢适应中的作用。利用果蝇可用的强大遗传工具，再加上分子、细胞、生理和高通量饮食中介的综合方法，我们将在生物组织的多个水平上定义这种相互作用。利用果蝇来探索代谢-先天性免疫相互作用的起源，对于提高发现新的疾病机制和药物靶点的速度具有巨大的希望，这些新的疾病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。

 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.