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

• 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
• 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

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.

项目摘要 哮喘是一种以气道高反应性（AHR）为特征的复杂疾病，预计会影响 到2025年，全球有4亿人。气道平滑肌（ASM）细胞是AHR的主要作用，如 他们夸大了对支气管收缩刺激的反应，并通过沉积来增加ASM厚度 细胞外基质和诱导注射。靶向表观遗传变化是一种新方法 扭转哮喘患者中看到的异常ASM表型。我们以前证明了全球DNA 在α-酮戊二酸（αkg）依赖性5-MC二氧酶（TET1）中介导的羟甲基化（TET1） 来自小鼠的肺组织，显示出升高过敏原诱导的AHR。此外，我们报道了一个新颖的作用 线粒体特异性异位酸脱氢酶2（IDH2）对人类ASM表型基因的调节 哮喘ASM细胞通过改变αkg水平和αkg依赖性TET1活性的改变，表明可能 细胞代谢与ASM细胞功能的表观遗传调节之间的联系。初步过敏原 - 诱导的AHR和异常的DNA羟基甲基化模式被线粒体靶向废除 四肽SS-31（Elamipretide，目前正在III期临床试验中用于治疗代谢疾病）。 此外，我们表明线粒体和表观基因组之间的相互作用是双向的。 鉴定出增加了参与线粒体复制和转录的基因的DNA羟甲基化增加， 与增加的AHR有关。我们的研究代表了TET1-的第一个证明 在线粒体功能的背景下，ASM中介导的DNA羟基甲基化受到调节，尽管 线粒体功能影响ASM细胞功能的表观遗传调节的机制，并且 反之亦然；尚未得到充分调查。基于这些新颖的发现，我们提出了中心假设 “线粒体氧化还原循环和生物能学的调节与表观遗传修饰的往复 ASM细胞功能，并最终改变哮喘发病机理”。为了解决这些新的假设，我们 组装一个跨越表观遗传学领域，氧化还原生物学领域的调查人员团队 和肺病学。首先，我们将确定线粒体功能的调节是否具有表观遗传学 对过敏原诱导的AHR的影响，SS-31可以减弱。其次，我们将研究是否表观遗传 线粒体转录的调节调节线粒体功能，这对 ASM细胞和AHR表型的表观基因组。最后，我们将确认线粒体斑点 利用临床样品确定ASM功能的相互作用。我们将采用相关分析 线粒体生物学的基因组分析和测量，以鉴定相关的分子标记集 哮喘严重程度。我们的发现应提供有关线粒体 - 观察串扰的新证据 ASM细胞和AHR相互作用的结果。这些见解可能会推动新的发展 治疗这种使人衰弱疾病的治疗方法。