Genetic Modeling of Diet, NFkB, and Metabolic Interactions

项目概要/摘要： 代谢和先天性免疫反应，两个原始系统的长期稳态的多- 细胞生物，已经进化到促进合作，适应性反应，对不同的环境 挑战不幸的是，营养过剩和饮食不平衡与病原体无关 （无菌）先天免疫信号传导途径激活，导致这些系统的错误调节， 代谢功能障碍和紊乱（如肥胖症和糖尿病）。NF-κ B转录因子，进化 先天免疫的保守调节因子，正在成为这种双向协调的关键节点， 代谢和先天免疫反应。揭示代谢系统的祖先整合 和NF-kB功能，由饮食和营养形成，从而促进了对基础生理学和 与代谢性疾病相关的复杂病因。本提案的总体目标是阐明 使用易处理的无脊椎动物模型构建以NF-kB为中心的先天免疫代谢信号网络框架 再加上基于细胞的哺乳动物模型。果蝇提供了强大的综合生理学模型 （在体内遗传学和饮食方面都是易于处理的）来建立这个框架;因为这些信号网络是 从昆虫到哺乳动物都有。主要利用果蝇，从以前的研究中获得新的见解 已经揭示了先天免疫转录因子NF-κ B在调节免疫应答中的进化保守作用。 在适应饮食变化过程中代谢靶基因的表达。发现NF-kB拮抗剂 Foxo功能（一种关键的营养响应转录因子）的表达对影响代谢靶基因至关重要， 不同的细胞类型以形成脂质代谢的不同方面（主要与卡替林的使用有关， 分解和动员）。这种拮抗作用随后平衡能量稳态与饮食依赖性 营养供应和促进代谢适应。这些发现强调了一个关键的需要，探索不同的 分子和细胞机制，由古老的先天免疫信号通路控制， 正常生理和病理之间的平衡与饮食介导的脂质破坏有关 新陈代谢.为此，可能是饮食和NF-κ B依赖性代谢转录拮抗作用， 因子功能可能是先天免疫-代谢信号网络整合的核心。有三 具体目标是这个建议：（i）探讨NF-κ B和组蛋白脱乙酰酶之间的相互作用，在控制 饮食依赖的染色质重塑和脂质代谢，（ii）以确定是否独特的信号 代谢靶点的饮食和NF-κ B依赖性转录衰减（vs激活）的直接机制 基因，和（ii）表征由饮食不平衡形成的NF-κ B调节的基因调控网络， 染色质重塑利用果蝇来探索先天免疫-代谢相互作用的起源 有望提高发现脂质代谢失衡的新机制的速度， 代谢功能障碍

Project Summary/Abstract: 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. Unfortunately, over-nutrition and dietary imbalances are associated with pathogen-independent (sterile) innate immune signaling pathway activation, leading to mis-regulation of these systems and instigating metabolic dysfunction and disorders (such as obesity and diabetes). NF-kB transcription factors, evolutionarily conserved regulators of innate immunity, are emerging as a critical node in this bidirectional coordination of metabolic and innate immune responses across taxa. Uncovering the ancestral integration of metabolic systems and NF-kB function, shaped by diet and nutrition, thus advances understanding of both basic physiology and the complex etiology associated with metabolic diseases. The overarching goal of this proposal is to elucidate a framework of NF-kB-centric innate immune-metabolic signaling networks using tractable invertebrate models coupled with cell-based mammalian models. Drosophila provide a powerful integrative physiology model (tractable both in terms of in vivo genetics and diets) to build this framework; as these signaling networks are conserved from insects to mammals. Mainly utilizing Drosophila, new insights derived from previous studies have revealed an evolutionarily conserved role for the innate immune transcription factor NF-kB in modulating metabolic target gene expression during adaptation to dietary changes. It was uncovered that NF-kB antagonism of Foxo function (a key nutrient-responsive transcription factor) is crucial to influence metabolic target genes in diverse cell types to shape distinctive aspects of lipid metabolism (largely linked to catabolism – usage, breakdown, and mobilization). This antagonism subsequently balances energy homeostasis with diet-dependent nutrient supply and promotes metabolic adaptation. These findings highlight a critical need to explore the distinct molecular and cellular mechanisms, governed by ancient innate immune signaling pathways, that may shape the equilibrium between normal physiology and pathology associated with diet-mediated disruptions in lipid metabolism. To this end, it is possible that diet- and NF-kB-dependent antagonism of metabolic transcription factor function may be central to the integration of innate immune-metabolic signaling networks. There are three specific aims to this proposal: (i) to explore interactions between NF-kB and histone deacetylases in the control of diet-dependent chromatin remodeling and lipid metabolism, (ii) to determine whether unique signaling mechanisms direct diet- and NF-kB-dependent transcriptional attenuation (vs activation) of metabolic target genes, and (ii) to characterize NF-kB-modulated gene regulatory networks shaped by dietary imbalances and chromatin remodeling. Exploiting Drosophila to explore the origin of innate immune-metabolic interactions holds promise for an enhanced rate of uncovering novel mechanisms that underly lipid-metabolic imbalances and metabolic dysfunction.