Foxo/NFkB Interactions in the Regulation of Metabolic Homeostasis

 描述（由申请人提供）：代谢和先天免疫反应是多细胞生物体长期稳态的两个关键原始系统，已进化为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导致代谢-先天免疫相互作用的失调和代谢疾病的发展，如肥胖和II型糖尿病。因此，迫切需要确定这些反应之间的机械联系和协调。我们研究的目标是使用果蝇作为一个简单的模型系统来揭示代谢-先天免疫相互作用的起源，以提高我们对人类饮食介导的代谢失衡的认识。在这个提议中，我们计划表征先天免疫转录因子NFkB和胰岛素响应性代谢转录因子Foxo之间的新型相互作用。NFkB转录因子是先天免疫的进化保守调节因子，正在成为代谢和先天免疫信号传导途径相互作用的双向通信和协调的关键节点。使用果蝇，一个重要的模式生物的代谢和综合生理学的研究，我们以前已经建立了Foxo转录功能的NF κ B介导的先天免疫反应的控制中的作用。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）中的饮食依赖性NFkB活性也可以通过调节Foxo功能影响脂质稳态;建立细胞Foxo/NFkB“稳态模块”，通过相互调节转录因子活性来控制代谢和先天免疫应答。果蝇提供了一个宝贵的，遗传学上可处理的模型来表征这个模块，因为这些信号网络是保守的从苍蝇到人类。有趣的是，果蝇脂肪体结合了营养和病原体感应器官的功能，突出了代谢状态和先天免疫功能之间的内在联系。该提议有三个具体目的：（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;和（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。使用强大的遗传工具，在果蝇，再加上整合的分子，细胞，生理和高通量饮食介导的方法，我们将定义这种相互作用在多个层次的生物组织。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型糖尿病等病理学的潜在代谢失衡。

 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.