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Mitochondrial-epigenetic crosstalk in regulation of airway hyperresponsiveness

线粒体表观遗传串扰调节气道高反应性

基本信息

批准号：
10687426
负责人：
Wan-yee Tang
金额：
$ 38.83万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2022-09-13 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10687426
关键词：
Acute Address Affect Allergens Asthma Attenuated Bioenergetics Biogenesis Biological Biology Bronchoconstrictor Agents Cardiolipins Cell Proliferation Cell physiology Cellular Metabolic Process Citric Acid Cycle Clinical Complex Cytosine DNA DNA Methylation DNA biosynthesis Data Analyses Deposition Development Dioxygenases Disease Enzymes Epigenetic Process Etiology Excision Exposure to Extracellular Matrix Future Generations Genes Genetic Transcription Genomics Human Individual Inflammation Intervention Isocitrate Dehydrogenase Link Long-Term Effects Measurement Mediating Metabolic Metabolic Diseases Mitochondria Mitochondrial DNA Modification Mus Muscle function Nature Nuclear Oxidation-Reduction Oxidative Phosphorylation Pathogenesis Pathway interactions Pattern Persons Phase III Clinical Trials Phenotype Process Production Proteins Pulmonology Pyroglyphidae Reaction Reactive Oxygen Species Regulation Reporting Research Research Personnel Risk Role Sampling Severities Smooth Muscle Myocytes Stimulus Structure of parenchyma of lung Symptoms TGFB2 gene Testing Thick Up-Regulation airway hyperresponsiveness airway inflammation airway remodeling alpha ketoglutarate asthma exacerbation asthmatic asthmatic airway smooth muscle base cell type effectiveness evaluation epigenetic regulation epigenome indoor allergen innovation insight mitochondrial genome molecular marker next generation sequencing novel novel strategies novel therapeutic intervention prevent respiratory smooth muscle response single-cell RNA sequencing therapeutic effectiveness

项目摘要

Project Summary Asthma is a complex disease characterized by airway hyperresponsiveness (AHR), which is expected to affect 400 million people worldwide by 2025. Airway smooth muscle (ASM) cells are the primary effectors of AHR, as they exaggerate the response to bronchoconstrictor stimuli and increase ASM thickness by depositing the extracellular matrix and inducing inflammation. Targeting epigenetic changes serves as a new approach to reversing the aberrant ASM phenotypes seen in asthmatics. We previously demonstrated that global DNA hydroxymethylation mediated by α-ketoglutarate (αKG)-dependent 5-mC dioxygenase (TET1) was induced in lung tissues from mice that showed increased allergen-induced AHR. In addition, we reported a novel role for mitochondrial-specific isocitrate dehydrogenase 2 (IDH2) on regulation of ASM phenotypic genes in human asthmatic ASM cells, through alterations in αKG level and αKG-dependent TET1 activity, suggesting a possible link between cell metabolism and epigenetic regulation of ASM cell function. Preliminarily, the allergen- induced AHR and aberrant DNA hydroxymethylation patterns was abolished by a mitochondrially targeted tetrapeptide, SS-31(elamipretide, which is currently in phase III clinical trials for treating metabolic diseases). Furthermore, we showed that the interaction between mitochondria and epigenome is bidirectional. We identified increased DNA hydroxymethylation of genes involved in mitochondrial replication and transcription, which was associated with the increased AHR. Our study represents the first demonstration that TET1- mediated DNA hydroxymethylation in ASM is regulated in the context of mitochondrial function, although the mechanisms by which mitochondrial function influences the epigenetic regulation of ASM cell function, and vice versa; have not been fully investigated. Based on these novel findings, we propose the central hypothesis “Modulation of mitochondrial redox cycling and bioenergetics reciprocates with the epigenetic modifications of the ASM cell function, and ultimately modifying asthma pathogenesis”. To address these novel hypotheses, we assemble a team of investigators with a breadth of expertise spanning the fields of epigenetics, redox biology and pulmonology. First, we will determine whether modulation of mitochondrial function has an epigenetic impact on allergen-induced AHR, which can be attenuated by SS-31. Second, we will study if epigenetic regulation of mitochondrial transcription modulates mitochondrial function, which has a long-term effect on the epigenome of the ASM cells and AHR phenotype. Finally, we will confirm the mitochondrial-epigenetic interplays in the determination of ASM function utilizing clinical samples. We will apply correlation analysis of genomic profiling and measurement of mitochondrial biology to identify sets of molecular markers associated with asthma severity. Our findings should provide new evidence about the mitochondrial-epigenetic crosstalk in ASM cells and the results of that interaction on AHR. These insights may fuel the development of new therapeutic approaches for the treatment of this debilitating disease.

项目总结