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： 新陈代谢和先天免疫反应，这两个原始系统对多发性骨髓瘤的长期稳态至关重要。 细胞生物，已经进化为促进对不同环境的合作和适应性反应 挑战。不幸的是，过度营养和饮食不平衡与病原体无关有关。 (不孕不育)先天免疫信号通路激活，导致这些系统的错误调节并煽动 代谢功能障碍和紊乱(如肥胖和糖尿病)。核因子-kB转录因子，进化 保守的先天免疫调节器，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。揭示新陈代谢系统的祖先整合 而由饮食和营养决定的核因子-kB功能，因此促进了对基本生理学和 与代谢性疾病相关的复杂病因。这项提案的首要目标是阐明一个 利用易处理的无脊椎动物模型构建以核因子-kB为中心的天然免疫-代谢信号网络框架 再加上基于细胞的哺乳动物模型。果蝇提供了一个强大的综合生理学模型 (在体内遗传学和饮食方面都是容易处理的)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保存着。主要利用果蝇，从以前的研究中获得新的见解 揭示了天然免疫转录因子核因子-kB在进化中的保守作用 代谢靶基因在适应饮食变化过程中的表达。已发现核因子-kB拮抗剂 FOXO功能(一种关键的营养响应转录因子)的表达是影响新陈代谢靶基因的关键 不同的细胞类型以形成脂代谢的不同方面(主要与分解代谢用途有关， 分解和动员)。这种对立随后平衡了能量动态平衡和饮食依赖。 营养供应和促进新陈代谢适应。这些发现突显了探索不同的 分子和细胞机制，由古老的先天免疫信号通路控制，可能会形成 饮食介导的脂质紊乱与正常生理和病理之间的平衡 新陈代谢。为此，有可能依赖饮食和核因子-kB的代谢转录的拮抗作用 因子功能可能是先天免疫-代谢信号网络整合的核心。一共有三个 这一建议的具体目的：(I)探讨对照组中核因子-kB和组蛋白脱乙酰基酶之间的相互作用 饮食依赖的染色质重塑和脂质代谢，(Ii)确定独特的信号 代谢靶点依赖饮食和核因子-kB的转录抑制(VS激活)机制 基因，以及(Ii)表征由饮食不平衡和 染色质重塑。利用果蝇探索先天性免疫-代谢相互作用的起源 有希望提高发现新机制的速度，这些新机制可能导致脂质代谢失衡和 代谢功能障碍。