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Dynamic Metabolic Reprogramming in Macrophages during Immune Response

免疫反应期间巨噬细胞的动态代谢重编程

基本信息

批准号：
10540831
负责人：
Jing Fan
金额：
$ 23.61万
依托单位：
MORGRIDGE INSTITUTE FOR RESEARCH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-09 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540831
关键词：
Acetyl Coenzyme A Autoimmune Diseases Automobile Driving Basic Science Cells Citric Acid Cycle Communicable Diseases Coupled Coupling Data Set Disease Failure Foundations Gene Expression Genes Goals Health Histone Acetylation Human Immune Immune Tolerance Immune response Immunity Inflammation Inflammatory Innate Immune System Interferon Type II Interferons Intervention Investigation Isotopes Knowledge Lead Lipopolysaccharides Mediating Metabolic Metabolic Pathway Metabolism Modification Molecular Nitric Oxide Nucleotides Pathway interactions Play Process Publishing Pyruvate Dehydrogenase Complex Reaction Regulation Research Resolution Role Specificity Statistical Data Interpretation Stimulus Structure System Testing Time Transcriptional Regulation Work arm chronic inflammatory disease follow-up immune function macrophage multiple omics novel nucleotide metabolism pathogen preference response tissue repair

项目摘要

Project Summary / Abstract The overarching goal of this project is to understand how cellular metabolism is dynamically reprogrammed in macrophages during immune responses, and how such metabolic reprogramming impacts immune functions. Emerging research indicates that metabolism plays a crucial role in supporting and orchestrating immunity. However, our understanding of macrophage metabolism is just beginning, and is largely limited to static comparisons of metabolic preferences associated with different activation states. Understanding time-dependent metabolic rewiring is of great significance because an immune response is a highly dynamic process, through which macrophages undergo a sequence of functional transitions that mediate the onset and resolution of inflammation. Proper regulation of macrophage responses is critical, as failure to activate or control macrophage functions at the appropriate times can lead to a variety of diseases. The integrative approach that we take to investigate dynamic metabolic rewiring during an immune response starts with a multi-omics characterization that reveals metabolic processes whose alteration is temporally coupled to functional transitions. This is followed by targeted perturbations to determine the impact of these metabolic alterations on immune functions. Then we perform isotopic tracing studies to quantitatively characterize how fluxes through these pathways change during immune responses and identify important regulatory points. Finally, in-depth molecular studies are used to elucidate the mechanisms driving these key metabolic alterations and the mechanisms by which such metabolic alterations orchestrate immune functions. Our preliminary work on the dynamic metabolic rewiring in macrophages upon LPS and interferon-γ stimulation revealed that alterations in TCA cycle and nucleotide metabolism are critical for this immune response. We discovered that metabolic fluxes through the TCA cycle undergo a two-stage remodeling and that inhibition of the pyruvate dehydrogenase complex (PDHC) drives the transition from early inflammatory stage to late suppressive stage. Building on this, aim 1 will investigate the molecular mechanism causing PDHC inhibition, and test the hypothesis that PDHC inhibition drives the transition into a more suppressive state and mediates immune tolerance by restricting acetyl-coA for histone acetylation. Aim 2 will focus on nucleotide metabolism to quantitatively study how nucleotide synthesis, degradation, and salvage fluxes change upon LPS and interferon-γ stimulation, and elucidate the mechanism driving such changes. Aim 3 will expand the scope of this proposal by characterizing the dynamic metabolic reprograming in response to a variety of other stimuli using multi-omics approaches. It will identify key metabolic transitions in each response and create a roadmap towards mechanistic understanding of the metabolism-immunity coupling. Overall, this proposal will elucidate the metabolic underpinnings of immune responses in macrophages, which has great importance in basic science and broad relevance to diseases where macrophages play a key role.

项目总结/摘要这个项目的首要目标是了解细胞代谢是如何动态地重新编程，免疫应答过程中的巨噬细胞，以及这种代谢重编程如何影响免疫功能。新兴的研究表明，新陈代谢在支持和协调免疫方面起着至关重要的作用。然而，我们对巨噬细胞代谢的理解才刚刚开始，并且在很大程度上限于静态的与不同激活状态相关的代谢偏好的比较。理解时间依赖性代谢重新布线具有重要意义，因为免疫反应是一个高度动态的过程，通过其中巨噬细胞经历一系列功能性转变，炎症适当调节巨噬细胞反应至关重要，因为不能激活或控制巨噬细胞功能在适当的时候可以导致各种疾病。我们采取的综合方法研究免疫应答过程中动态代谢重新连接始于多组学表征它揭示了代谢过程，这些代谢过程的改变在时间上与功能转变相关联。紧随其后的通过有针对性的扰动来确定这些代谢改变对免疫功能的影响。然后我们进行同位素示踪研究，以定量地描述这些途径的通量在免疫反应和确定重要的调控点。最后，深入的分子研究被用来阐明驱动这些关键代谢改变的机制以及这些代谢改变的机制，改变协调免疫功能。我们对脑内动态代谢重组的初步研究巨噬细胞在LPS和干扰素-γ刺激后显示TCA循环和核苷酸的改变，代谢对于这种免疫反应至关重要。我们发现TCA循环中的代谢通量经历两个阶段的重塑，并且丙酮酸脱氢酶复合物（PDHC）的抑制驱动从早期炎症阶段过渡到晚期抑制阶段。在此基础上，aim 1将调查分子机制引起的PDHC抑制，并测试的假设，PDHC抑制驱动转换进入更抑制的状态，并通过限制乙酰辅酶A进行组蛋白乙酰化来介导免疫耐受。目标2将集中在核苷酸代谢，定量研究核苷酸的合成，降解，补救流量的变化后，LPS和干扰素-γ刺激，并阐明了驱动机制，变化目标3将通过表征在细胞内的动态代谢重编程来扩展该提议的范围。使用多组学方法对各种其他刺激的反应。它将确定关键的代谢转换，每一个反应，并创建一个路线图对代谢免疫耦合的机制的理解。总的来说，这项提议将阐明巨噬细胞免疫反应的代谢基础，在基础科学中具有重要意义，并且与巨噬细胞发挥关键作用的疾病具有广泛的相关性。