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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.

摘要