Genetic Modeling of Diet, NFkB, and Metabolic Interactions

饮食、NFkB 和代谢相互作用的遗传建模

• 批准号: 10501274
• 负责人: Jason S Karpac
• 金额: $ 37.59万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501274
• 关键词: Acute; Address; Animals; Architecture; Attenuated; Binding; Biological Models; Calories; Catabolism; Cells; Chromatin; Chromatin Remodeling Factor; Chronic; Complex; Coupled; DNA-Directed RNA Polymerase; Development; Diabetes Mellitus; Diet; Diet Habits; Diet and Nutrition; Drosophila genus; Drosophila melanogaster; Equilibrium; Etiology; Gene Expression; Genes; Genetic; Genetic Models; Genetic Screening; Genetic Transcription; Genomics; Goals; Histone Deacetylase; Homeostasis; Human; Immune; Immune Targeting; Immune signaling; In Vitro; Infection; Innate Immune Response; Insecta; Insulin; Invertebrates; Knowledge; Link; Lipids; Macronutrients Nutrition; Mammals; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Modeling; Modernization; Molecular; Molecular Biology; NF-kappa B; Natural Immunity; Nucleic Acid Regulatory Sequences; Nutrient; Obesity; Organism; Overnutrition; Pathology; Physiology; Regulation; Research; Role; Sense Organs; Shapes; Signal Pathway; Signal Transduction; Starvation; Sterility; System; Testing; Tissues; Transcriptional Activation; antagonist; attenuation; base; biological adaptation to stress; cell type; chromatin modification; chromatin remodeling; combat; dietary; dietary control; energy balance; functional genomics; gene induction; gene regulatory network; genome-wide; genomic locus; in vivo; innate immune function; insight; lipid metabolism; novel; nutrition; pathogen; recruit; response; screening; stressor; transcription factor

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.

项目摘要/摘要： 代谢和先天免疫反应，这两个原始系统对于多细胞的长期稳态至关重要 细胞生物体已经进化到促进针对不同环境的合作性、适应性反应 挑战。不幸的是，营养过剩和饮食失衡与病原体无关的疾病有关。 （无菌）先天免疫信号通路激活，导致这些系统的错误调节并煽动 代谢功能障碍和疾病（例如肥胖和糖尿病）。 NF-kB 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 跨类群的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，由饮食和营养决定，从而增进对基本生理学和 与代谢疾病相关的复杂病因。该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 与基于细胞的哺乳动物模型相结合。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易于处理）建立这个框架；因为这些信号网络是 从昆虫到哺乳动物都是保守的。主要利用果蝇，从之前的研究中得出新的见解 揭示了先天免疫转录因子 NF-kB 在调节中的进化保守作用 适应饮食变化期间的代谢靶基因表达。研究发现，NF-kB具有拮抗作用 Foxo 功能（一种关键的营养响应转录因子）对于影响代谢靶基因至关重要 不同的细胞类型塑造脂质代谢的独特方面（很大程度上与分解代谢有关 - 使用， 崩溃和动员）。这种拮抗作用随后平衡了能量稳态与饮食依赖性 营养供应并促进代谢适应。这些发现凸显了探索独特的迫切需要 由古老的先天免疫信号通路控制的分子和细胞机制，可能会塑造 与饮食介导的脂质破坏相关的正常生理学和病理学之间的平衡 代谢。为此，代谢转录的饮食和 NF-kB 依赖性拮抗作用可能 因子功能可能是先天免疫代谢信号网络整合的核心。有三个 该提案的具体目标：（i）探索对照中 NF-kB 和组蛋白脱乙酰酶之间的相互作用 饮食依赖性染色质重塑和脂质代谢，(ii) 确定是否有独特的信号传导 代谢靶标的直接饮食和 NF-kB 依赖性转录减弱（与激活）的机制 基因，以及 (ii) 表征由饮食不平衡和 NF-kB 调节的基因调控网络 染色质重塑。利用果蝇探索先天免疫代谢相互作用的起源是正确的 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。