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Genetic and metabolic regulation of macrophage activation at steady state

巨噬细胞稳态激活的遗传和代谢调控

基本信息

批准号：
10809141
负责人：
Celia E Shiau
金额：
$ 1.03万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10809141
关键词：
Address Adopted Area Biological Cells Chronic Circulation Clustered Regularly Interspaced Short Palindromic Repeats Complex Development Diabetes Mellitus Disease Disparate Engineering Ensure Excision Genes Genetic Genetic Engineering Genetic Screening Glycolysis Health Human Inflammation Inflammatory Innate Immune System Intestines Knowledge Kupffer Cells Logic Macrophage Macrophage Activation Malignant Neoplasms Metabolic Metabolism Microglia Molecular Mutation Normal tissue morphology Obesity Organ Oxidative Phosphorylation Play Process Property Proteomics Public Health Regulation Research Technology Tissues Work Zebrafish autoinflammatory design disorder prevention genetic manipulation high throughput screening human disease in vivo in vivo imaging insight metabolomics monocyte novel pathogen programs protein protein interaction receptor technology development tissue repair transcriptomics whole body imaging

项目摘要

Project Summary Inflammation is essential for tissue repair and removal of harmful pathogens and molecules, but if activated inappropriately, the innate immune system triggers autoinflammatory conditions. Macrophages play a key role in inflammation and have tremendous impact on human health, both positive and negative, yet many questions about these cells remain unanswered. They are heterogeneous and adopt a spectrum of activation states, both as distinct tissue-resident macrophages and in circulation as monocytes. The drivers of these activation states remain elusive. Metabolism plays a role, with macrophages undergoing metabolic changes during proinflammatory activation, including switching from oxidative phosphorylation to glycolysis. However, whether metabolism or other intracellular processes alone can dictate activation states remains unclear and is critical to understanding a host of human diseases associated with inappropriate inflammation. The current proposed research program addresses this question and significantly expands our previous work. We are leveraging the unique advantages zebrafish provide for exquisite genetic manipulations, high throughput screening, and in vivo imaging to dissect the complex relationship between intracellular processes and macrophage activation. The discovery of an inactivating mutation in a NOD-like receptor, nlrc3l, that causes inappropriate macrophage activation and loss of microglia led us to create a new genetic screen in zebrafish that yielded several novel macrophage mutations that we will investigate. These new mutations cause inappropriate macrophage activation, disrupt microglia development or both. We are investigating whether nlrc3l and associated genes as well as new genes we identify from the screen regulate macrophage activation by altering metabolic and other intracellular processes. We are taking an integrated approach at multiple levels—using differential transcriptomics, proteomics, and metabolomics, high power in vivo single cellular and whole-body imaging, CRISPR based genetic engineering, protein-protein interactions, and cross-species experimentations—to address these questions. Furthermore, our previous results raise critical new questions regarding how activation states are regulated to ensure normal tissue macrophage development, and whether common mechanisms exist to control macrophage activation across multiple organs. Our research program will expand to address these key areas in vivo using a diverse set of tissue macrophages (microglia, intestinal macrophages, and Kupffer cells). These studies aim to provide necessary insights into macrophage differentiation, plasticity, and potential in a disease-relevant context, and address how seemingly disparate functions (development and activation regulation) are encoded in the molecular program governing macrophages. In summary, our research will lead to new knowledge and technologies needed to harness the properties of macrophages for disease prevention and treatment.

项目摘要炎症对于组织修复和有害病原体和分子的清除是必不可少的，但如果被激活不合时宜的是，先天免疫系统会引发自体炎症。巨噬细胞扮演着关键角色并对人类健康产生了巨大的影响，既有积极的，也有消极的，但仍存在许多问题关于这些细胞的问题仍未得到答复。它们是异质的，并采用一种激活状态的光谱，两者作为独特的组织驻留巨噬细胞，并作为单核细胞在循环中。这些激活状态的驱动因素仍然难以捉摸。代谢起着一定的作用，巨噬细胞在前炎性激活，包括从氧化磷酸化转换为糖酵解。然而，无论是新陈代谢或其他细胞内过程本身就可以决定激活状态，目前尚不清楚，这对了解与不适当的炎症有关的一系列人类疾病。目前建议的研究计划解决了这个问题，并极大地扩展了我们之前的工作。我们正在利用斑马鱼提供的独特优势进行精巧的遗传操作，高产量筛选和体内成像以剖析细胞内过程和细胞内过程之间的复杂关系巨噬细胞激活。在Nod样受体nlrc3l中发现了一种失活突变，它导致不适当的巨噬细胞激活和小胶质细胞的丢失导致我们在斑马鱼中创建了一种新的基因筛查产生了几个新的巨噬细胞突变，我们将进行研究。这些新的突变导致了不适当的巨噬细胞激活，破坏小胶质细胞发育，或两者兼而有之。我们正在调查nlrc3l和相关基因以及我们从筛选中发现的新基因通过改变代谢和其他细胞内过程。我们正在多个层面采取综合方法--使用差异转录组学、蛋白质组学和代谢组学，体内单细胞和整体的高功率成像、基于CRISPR的基因工程、蛋白质-蛋白质相互作用和跨物种实验--来解决这些问题。此外，我们之前的结果提出了关键的新问题关于如何调节激活状态以确保组织巨噬细胞的正常发育，以及存在控制多个器官的巨噬细胞激活的共同机制。我们的研究计划将使用一组不同的组织巨噬细胞(小胶质细胞、肠道细胞)扩展以解决体内这些关键区域巨噬细胞和库普弗细胞)。这些研究旨在提供对巨噬细胞的必要见解。疾病相关背景下的差异性、可塑性和潜力，并解决看似不同的问题功能(发育和激活调节)编码在分子程序管理中巨噬细胞。总而言之，我们的研究将带来利用巨噬细胞用于疾病预防和治疗的特性。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Zebrafish harbor diverse intestinal macrophage populations including a subset intimately associated with enteric neural processes.

DOI：
10.1016/j.isci.2021.102496
发表时间：
2021-06-25
期刊：
iScience
影响因子：
5.8
作者：
Graves CL;Chen A;Kwon V;Shiau CE
通讯作者：
Shiau CE

Liposomal Clodronate-mediated Macrophage Depletion in the Zebrafish Model.

斑马鱼模型中脂质体氯膦酸盐介导的巨噬细胞耗竭。

DOI：
10.21769/bioprotoc.3951
发表时间：
2021
期刊：
Bio-protocol
影响因子：
0.8
作者：
Yang,Linlin;Rojas,AlisonM;Shiau,CeliaE
通讯作者：
Shiau,CeliaE

Peripheral NOD-like receptor deficient inflammatory macrophages trigger neutrophil infiltration into the brain disrupting daytime locomotion.

DOI：
10.1038/s42003-022-03410-z
发表时间：
2022-05-16
期刊：
COMMUNICATIONS BIOLOGY
影响因子：
5.9
作者：
Kwon, Victoria;Cai, Peiwen;Dixon, Cameron T.;Hamlin, Victoria;Spencer, Caroline G.;Rojas, Alison M.;Shiau, Celia E.
通讯作者：
Shiau, Celia E.

Critical Role for a Subset of Intestinal Macrophages in Shaping Gut Microbiota in Adult Zebrafish.