Dysregulated Immunometabolism and Premature Senescence in Corticosteroid-Refractory Severe Asthma

皮质类固醇难治性严重哮喘的免疫代谢失调和过早衰老

• 批准号: 10567868
• 负责人: Anuradha Ray
• 金额: $ 74.34万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2030-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567868
• 关键词: Address; Adrenal Cortex Hormones; Adult; Allergens; Asthma; Belief; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cell Aging; Cells; Child; Chronic Disease; Chronic Obstructive Pulmonary Disease; Chronic lung disease; Clinical; Development; Dose; Funding; Generations; Glucocorticoid Receptor; Goals; Human; Immune; Immune System Diseases; Immune response; Immunology; Inflammaging; Inflammatory; Inhalation; Interferon Type II; Laboratories; Lipids; Literature; Lung; Lung diseases; Metabolism; Molecular; Molecular Biology; Pathogenesis; Patients; Phenotype; Premature aging syndrome; Production; Refractory; Research; STAT1 gene; Scientist; Side; Stress; T-Lymphocyte; Th2 Cells; Therapeutic; Therapeutic Intervention; Training; allergic airway disease; asthmatic patient; disease heterogeneity; flexibility; high dimensionality; human old age (65+); idiopathic pulmonary fibrosis; improved; in vivo; interest; mitochondrial dysfunction; mouse model; multiple omics; new therapeutic target; novel therapeutics; peripheral blood; premature; prevent; programs; response; senescence; targeted treatment; tissue resident memory T cell; tool; treatment response

Our laboratory has been engaged in elucidating mechanisms of asthma pathogenesis for over two decades. These efforts resulted in the discovery of GATA-3 as the key molecular regulator of development of Th2 cells that promote allergic airway disease. Since our initial discovery, GATA-3 was successfully targeted in allergen- induced mild asthma in humans. While Th2-driven mild asthma is well recognized and therapeutically manageable with inhaled corticosteroids (CS), 5-10% of asthma is clinically deemed severe and these patients poorly respond to CS, even when used in large doses. To address this issue of disease heterogeneity and identify the underlying mechanisms, we have studied the airway immune cells of severe asthma (SA) patients using various tools of immunology and molecular biology including a high dimensional multi-omics approach. Side-by-side we have used new mouse models of SA established in our laboratory to validate potential targets for therapeutic intervention in vivo. These studies have led to another original and unexpected finding of a high IFN-g response (Type 1/T1 response) in bronchoalveolar lavage (BAL) T cells in a subset of SA patients, a large fraction of these T cells having features of tissue resident memory T cells (TRMs). A T1high immune response is increasingly being appreciated in SA in both children and adults in independent studies challenging the belief that IFN-g is always protective in asthma since it cross-regulates a T2 immune response. We have also identified a deleterious feed forward positive loop induced by CS due to co-operation between STAT1, downstream of IFN-g, and the glucocorticoid receptor (GR) that would cause unremitting IFN-g production in the airways. The ramifications of unremitting IFN-g production can be profound and damaging given its potential to induce cellular senescence. Intimately associated with the T1high immune response is also cellular metabolism since mitochondrial dysfunction results in high levels of IFN-g production. Emerging literature provides strong evidence of mitochondrial dysfunction in immune cells resulting in senescence and inflammaging. While replicative senescence and inflammaging are typically associated with old age, the notion of stress-induced premature senescence (SIPS) causing premature aging and decline is being entertained in lung diseases including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Since IFN-g can induce senescence in surrounding cells, the driver of SIPS may be inflammatory immune cells, especially T1high TRMs. The key goal of the proposed research program is to interrogate lung and peripheral blood immune cells and lipids in the BAL fluid of patients to identify mechanisms that induce a CS- refractory inflammatory phenotype in SA. We believe our studies would identify novel therapeutic targets to prevent SIPS in SA which may have relevance in other lung diseases. The long-term funding and flexibility of the R35 mechanism will help me to continue to train a new generation of scientists interested in studying immune dysfunction to develop novel therapies for recalcitrant chronic lung diseases that can induce SIPS.

我们的实验室二十多年来一直致力于阐明哮喘发病机制。 这些努力导致发现 GATA-3 作为 Th2 细胞发育的关键分子调节因子 促进过敏性气道疾病。自我们最初发现以来，GATA-3 已成功针对过敏原 诱发人类轻度哮喘。虽然 Th2 驱动的轻度哮喘已得到充分认识和治疗 通过吸入皮质类固醇 (CS) 即可控制，5-10% 的哮喘临床上被认为是严重的，这些患者 即使大剂量使用，对 CS 的反应也很差。为了解决疾病异质性问题 确定潜在机制，我们研究了严重哮喘（SA）患者的气道免疫细胞 使用各种免疫学和分子生物学工具，包括高维多组学方法。 同时，我们还使用我们实验室建立的新 SA 小鼠模型来验证潜在目标 用于体内治疗干预。这些研究带来了另一个原创且意想不到的发现： SA 患者子集的支气管肺泡灌洗 (BAL) T 细胞中的 IFN-g 反应（1 型/T1 反应） 这些 T 细胞中的很大一部分具有组织驻留记忆 T 细胞 (TRM) 的特征。 A T1高免疫 在独立研究中，南非儿童和成人的反应越来越受到重视 挑战 IFN-g 对哮喘始终具有保护作用的观点，因为它交叉调节 T2 免疫反应。 我们还发现了由于 CS 之间的合作而引起的有害前馈正循环 STAT1，IFN-g 的下游，以及会导致不间断的 IFN-g 的糖皮质激素受体 (GR) 气道中的生产。不断产生 IFN-g 的后果可能是深远且具有破坏性的 鉴于其诱导细胞衰老的潜力。与 T1 高免疫反应也密切相关 细胞代谢，因为线粒体功能障碍导致高水平的 IFN-g 产生。新兴 文献提供了强有力的证据表明免疫细胞线粒体功能障碍导致衰老和 发炎。虽然复制性衰老和炎症通常与老年有关，但这一概念 压力诱发的早衰（SIPS）导致过早衰老和衰退的研究正在被人们所接受。 肺部疾病包括特发性肺纤维化（IPF）和慢性阻塞性肺病（COPD）。 由于 IFN-g 可以诱导周围细胞衰老，因此 SIPS 的驱动因素可能是炎症免疫 细胞，尤其是 T1high TRM。拟议研究计划的主要目标是研究肺和 患者 BAL 液中的外周血免疫细胞和脂质，以确定诱导 CS-的机制 SA 中的难治性炎症表型。我们相信我们的研究将确定新的治疗靶点 预防 SA 中的 SIPS，这可能与其他肺部疾病有关。长期资金和灵活性 R35机制将帮助我继续培养有兴趣研究的新一代科学家 免疫功能障碍，开发针对可诱发 SIPS 的顽固性慢性肺部疾病的新疗法。