Transcriptional and metabolomic regulation of IL-10 in pulmonary ILC2s

肺ILC2中IL-10的转录和代谢组调节

基本信息

批准号：
10582029
负责人：
OMID AKBARI
金额：
$ 41.25万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
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：
2022-09-20 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10582029
关键词：
Acute Address Agonist Allergen Immunotherapy Allergens Allergic Allergic Disease Alternaria Anti-Inflammatory Agents Asthma Bioenergetics Biological Assay Cells Chromatin Chronic Clinical Data Disease Disease model Energy-Generating Resources Enhancers Event Extrinsic asthma Generations Genes Genetic Transcription Genus Hippocampus Glycolysis Goals Health Care Costs High-Throughput Nucleotide Sequencing Hypersensitivity Immune Immune response Immunity In Vitro Infiltration Inflammation Inflammatory Intention Interleukin-10 Interleukin-13 Interleukin-5 Knockout Mice Laboratories Link Lung Lymphoid Cell Measures Metabolic Metabolic Pathway Metabolism Methods Mitochondria Modeling Modification Molecular Morbidity - disease rate Morphology Oxidative Phosphorylation Pathogenicity Patients Play Population Process Production Property Publishing Pulmonary Inflammation Regulation Research Respiratory Disease Role Series Severities Signal Transduction Signaling Protein Source Structure of parenchyma of lung Symptoms Technology Transcriptional Regulation Translating airway hyperresponsiveness airway inflammation allergic airway inflammation antagonist asthma model base cell type cytokine design energy balance eosinophil experimental study fatty acid oxidation improved in vivo insight metabolomics mouse model novel novel therapeutic intervention novel therapeutics overexpression tissue injury transcription factor translational approach

项目摘要

Abstract ILC2s are the dominant innate lymphoid cell population in the lungs at steady state and their release of type-2 cytokines is a central driver in responding eosinophil infiltration, increased airway hyperreactivity and associated lung tissue injury. Previously, our laboratory identified a subset of ILC2s (ILC210s) that actively produce and secrete IL-10, an anti-inflammatory cytokine with the ability to ameliorate allergic lung inflammation signaling (J Allergy Clin Immunol., 2020). Importantly, these results have been confirmed by other groups in a variety of allergic disease models (J Exp Med., 2020, Immunity, 2021). The proposed research plan is motivated by recent preliminary observations demonstrating that key molecular and transcriptional requirements may be required for the induction of IL-10, with the potential for targeted modulation. SA1 is intended to explore the regulation of transcription factors for the induction of IL-10. We propose a series of experiments in acute and chronic models of allergic airway inflammation to assess the involvement of key transcription factors cMaf and Blimp-1 first by expansive, cutting-edge chromatin sequencing methods, and next by retroviral induction and knock-out mouse models. In SA2, we also observed that production of IL-10 relies significantly on key metabolic pathways often utilized by ILC2s. We intend to expand our studies by investigating the role of glycolysis, fatty acid oxidation and signaling protein AMPK, with the aim of identifying mechanistic targets for the potential modulatory therapies for allergic disease. Additionally, mitochondrial regulation of IL-10 production with be explored through in vitro and ex vivo mitochondrial dynamic assays. Finally, the two parts of this project come together to address specific transcriptional and metabolic requirements for the modulation of pathogenic ILC2s with the intention of targeted conversion to ILC210s with the ability to regulate airway hyperreactivity. The results obtained from this study will provide novel insights into an important and understudied role of ILC210s in diseases associated with ILC2s such as allergic lung inflammation and asthma.

抽象的 ILC2是稳态下肺中的主要先天淋巴样细胞群，它们的释放2型细胞因子是反应嗜酸性粒细胞浸润，气道高反应性和相关性的核心驱动力肺组织损伤。以前，我们的实验室确定了积极生产和分泌IL-10，一种具有改善过敏性肺部炎症信号传导能力的抗炎细胞因子（J 过敏临床免疫，2020年）。重要的是，这些结果已由其他各个小组确认过敏疾病模型（J Exp Med。，2020年，免疫，2021年）。拟议的研究计划是由最近的初步观察表明，关键分子和转录要求可能是诱导IL-10所需的，具有靶向调制的潜力。 SA1旨在探索调节转录因子的诱导IL-10。我们提出了一系列急性实验过敏性气道炎症的慢性模型，以评估关键转录因子CMAF和首先是由膨胀的，尖端的染色质测序方法，然后是逆转录病毒诱导和敲除鼠标模型。在SA2中，我们还观察到IL-10的产生显着取决于关键代谢 ILC2通常使用的途径。我们打算通过研究糖酵解，脂肪的作用来扩展我们的研究酸性氧化和信号蛋白AMPK，目的是识别电势的机械目标过敏性疾病的调节疗法。此外，用BE对IL-10产生的线粒体调节通过体外和体内线粒体动态测定进行探索。最后，这个项目的两个部分来了共同解决致病性ILC2S调制的特定转录和代谢要求目的是将靶向转换为ILC210，并具有调节气道高反应性的能力。结果从这项研究中获得的将为ILC210在疾病中的重要而研究的作用提供新的见解与诸如过敏性肺部炎症和哮喘等ILC2相关。