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Mitochondrial Biogenesis is Regulated by RelB During Inflammation

炎症过程中线粒体生物合成受 RelB 调节

基本信息

批准号：
9265879
负责人：
Charles Emory McCall
金额：
$ 29.45万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-05 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9265879
关键词：
Affect Alpha Cell Anabolism Binding Biochemical Bioenergetics Biogenesis Biological Assay Catabolism Cell Respiration Cells Cellular biology Cessation of life Complex DNA DNA Methylation DNA-Directed RNA Polymerase Data Deacetylase Disease Electron Transport Electrons Enhancers Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Glucose Glycolysis Goals Homeostasis Human Immune Immune response Immunity Immunosuppression Immunosuppressive Agents Impairment Incidence Inflammation Kinetics Leukocytes Lipolysis Metabolism Mitochondria Mitochondrial DNA Mitochondrial Proteins Mitochondrial RNA Modeling Molecular Mus Muscle Myelogenous NF-kappa B Natural Immunity Nuclear Outcome Pathway interactions Pharmaceutical Preparations Phase Phenotype Physiology Process Publishing Respiration Role SIRT1 gene Sepsis Splenocyte Testing Transcriptional Regulation Translational Research antiporter base chromatin immunoprecipitation design economic impact fatty acid oxidation gain of function global health immunosuppressed improved knock-down macrophage mitochondrial metabolism monocyte oligomycin sensitivity-conferring protein outcome forecast oxidation promoter public health relevance response septic tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): The goal of this proposal is to determine how alterations in mitochondrial metabolism and bioenergetics influence the immunosuppressive phase of sepsis. Sepsis incidence is rising, there are no specific therapies, and most deaths occur during the phase of immunosuppression that follows hyperinflammation. We discovered using a cell-based model of sepsis and human sepsis blood leukocytes that NAD+-dependent deacetylase Sirtuin 1 (Sirt1) activates NF-kB factor RelB to switch proinflammation to immunosuppression, reduce glucose-dependent anabolic pathways and increase catabolic lipolysis and mitochondrial fatty acid oxidation. We also find that Sirt1-activated RelB induces expression of mitochondrial regulator Sirt3, which as a mitochondrial protein promotes catabolic fatty acid oxidation and mitochondrial respiration. Moreover, RelB translocates to mitochondria, binds mitochondrial promoter DNA, and increases transcription of mitochondrial genes. Remarkably, Sirt1 inhibition markedly improves survival of septic mice when administered during the immunosuppressive phase. Substantial data support that switching from anabolism to catabolism can compromise glucose-dependent effector immune responses. Based on these collective data: This proposal will test the hypothesis that protracted Sirt1 activation adversely affects sepsis outcome through a Sirt1-RelB-Sirt3 nuclear-mitochondrial axis (here, called the Sirt1 axis) to decrease net anabolic and increase net catabolic metabolism in myeloid-derived innate immune cells. We have designed 3 aims to explore this new concept: Aim 1: Determine whether Sirt1 axis activation alters mitochondrial metabolism and bioenergetics during sepsis immunosuppression. Aim 2: Determine how mitochondrial gene expression and the electron transport chain are regulated by the Sirt1 axis during the immunosuppressed phase of sepsis. Aim 3: Define how Sirt1 and RelB regulate Sirt3 expression. Approach: Cell-based, murine and human sepsis responses will be investigated using state-of-the art biochemical, molecular cell biology, and genetics tools. Impact: Completing these aims will define the role of the Sirt1 axis in sepsis immunosuppression of innate immunity, identify precise mitochondrial and nuclear processes controlled by the Sirt1 axis, and introduce a new way to treat the disease by rebalancing the net function of the immunometabolic axis.

描述（由申请人提供）：本提案的目的是确定线粒体代谢和生物能量学的改变如何影响脓毒症的免疫抑制阶段。脓毒症的发病率正在上升，没有特定的治疗方法，大多数死亡发生在炎症过度后的免疫抑制阶段。我们发现，使用基于细胞的脓毒症和人脓毒症血液白细胞模型，NAD+依赖性脱乙酰酶Sirtuin 1（Sirt 1）激活NF-κ B因子RelB，将促炎症转换为免疫抑制，减少葡萄糖依赖性合成代谢途径，增加分解代谢脂解和线粒体脂肪酸氧化。我们还发现，Sirt 1激活的RelB诱导线粒体调节因子Sirt 3的表达，Sirt 3作为线粒体蛋白促进分解代谢脂肪酸氧化和线粒体呼吸。此外，RelB易位到线粒体，结合线粒体启动子DNA，并增加线粒体基因的转录。值得注意的是，当在免疫抑制阶段施用时，Sirt 1抑制显著改善脓毒症小鼠的存活率。大量数据支持从安替洛尔转换为卡替洛尔可损害葡萄糖依赖性效应免疫应答。基于这些收集的数据：该提案将测试这样的假设，即Sirt 1的长期激活通过Sirt 1-RelB-Sirt 3核-线粒体轴（这里称为Sirt 1轴）对脓毒症的结果产生不利影响，以减少髓源性先天免疫细胞的净合成代谢和增加净分解代谢。我们设计了3个目的来探索这个新概念：目的1：确定Sirt 1轴激活是否改变脓毒症免疫抑制过程中的线粒体代谢和生物能量学。目标二：确定线粒体基因表达和电子传递链是如何调节的Sirt 1轴在脓毒症的免疫抑制阶段。目的3：明确Sirt 1和RelB如何调控Sirt 3的表达。方法：将使用最先进的生物化学、分子细胞生物学和遗传学工具研究基于细胞的鼠和人脓毒症反应。影响：完成这些目标将确定Sirt 1轴在先天免疫的脓毒症免疫抑制中的作用，确定由Sirt 1轴控制的精确线粒体和核过程，并通过重新平衡免疫代谢轴的净功能引入治疗疾病的新方法。