Molecular and Cellular Dissection of miRNAs in Controlling Allergic Airway Inflammation in Mice

miRNA 在控制小鼠过敏性气道炎症中的分子和细胞解析

• 批准号: 10664926
• 负责人: DAVID B CORRY
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10664926
• 关键词: Affect; Airway Disease; Allergens; Allergic; Allergic Disease; Allergic inflammation; Antifungal Agents; Antigen-Presenting Cells; Antigens; Aspergillus niger; Asthma; C-Type Lectins; CD11c Antigens; CD4 Positive T Lymphocytes; Cells; Chronic; Complex; Cytoprotection; Dendritic Cells; Dendritic cell activation; Detection; Development; Disease; Dissection; Epithelial Cells; Exposure to; Extrinsic asthma; FOXO1A gene; Family; Fungal Spores; Gene Expression; Genetic; Goals; Human; ITGAX gene; IgE; Immune response; In Vitro; Inflammatory; Inhalation; Interleukin-10; Interleukin-13; Knockout Mice; Laboratories; Lung; Lymphocyte; Mediating; Methods; MicroRNAs; Molecular; Molecular Analysis; Mus; Myeloid Cells; Pathogenesis; Pathologic; Pathway interactions; Patients; Pattern recognition receptor; Peptide Hydrolases; Production; Proteinase-Activated Receptors; Pulmonary Inflammation; Refractory; Regulation; Repression; Role; Severity of illness; Sorting; Testing; Therapeutic; Transgenic Mice; Veterans; airway epithelium; airway hyperresponsiveness; airway inflammation; airway remodeling; allergic airway disease; allergic airway inflammation; asthmatic; asthmatic patient; chronic inflammatory lung disease; combat veteran; conditional knockout; cytokine; disorder control; fungus; genetic element; genome-wide; global health; improved; in vivo; insight; member; mouse model; novel diagnostics; novel strategies; novel therapeutics; programs; response; specific biomarkers; standard care; success; tool; transcriptome

The long-term objective of our laboratory is to understand the underlying molecular and genetic causes for chronic allergic airway inflammation or asthma to improve therapeutic approaches. The specific objective of this application is to dissect microRNA (miRNA)-dependent inflammatory pathways in dendritic cells (DCs) and CD4+ T cells that modulate murine allergic airway disease to fungal allergens. Asthma is a major rising global health threat that disproportionately affects combat veterans. We showed that patients with asthma often have evidence of airway mycosis, defined as detection of fungi in airway secretions in association with specific biomarkers (e.g. IgE or TH2 cells) reactive to one or more fungi. Our laboratory and others have shown that fungal proteinases and fungal spores drive asthma-like airway disease in mice. Airway epithelial cells express pattern recognition receptors (PRRs) for foreign antigens (e.g. TLRs, C-type lectin, and protease-activated receptors) and important for conventional dendritic cell (cDC) activation and initiation of allergic CD4+ type 2 cell (TH2) and TH17 cell-dependent airway inflammation, IgE production, and airway hyperresponsiveness (AHR), collectively termed allergic airway disease. We and others have shown the requirement of TH2 cells and DC in the pathogenesis of allergic airway disease. We employed murine models of chronic allergic airway inflammation, and detected aberrant expression of let-7 miRNA family in lung, CD4+ T cells and CD11c+ DCs. Specifically, the expression of let-7b and let-7c (let-7bc-cluster) is reduced in sorted lung CD4+ T cells and enhanced in CD11c+ antigen presenting cells (APCs) of mice with chronic allergic airway disease. Moreover, mice that lack the let-7bc-cluster globally or specifically in CD4+ T cells or CD11c+ APCs show blunted TH2 responses and allergic disease. On the other hand enforced expression of let-7 specifically in CD4+ T cells enhances fungus-induced allergic airway disease. The let-7b and let-7c members only account for only 9% of total let-7 activity in lymphocytes and myeloid cells suggesting that let-7bc cluster critically determines gene expression of CD4+ T cells and DCs that drive allergic sensitization to Aspergillus niger. Our central hypothesis therefore states that the let-7 family modulates allergic airway disease severity and orchestrates activation of cDCs and TH2 responses. We will address this hypothesis through the following Specific Aims: 1) Elucidate the CD4+ T cell intrinsic requirement of the let-7bc-cluster in pathogenesis of allergic airway disease. Hypothesis: The let-7bc-cluster regulates target gene expression in CD4+ T cells and controls TH2 lung inflammation and allergic airway disease. 2) Determine the role of let-7bc-cluster in DC-mediated control of allergic airway inflammation. Hypothesis: Induction of let-7bc-cluster expression in asthmatic lung cDCs directs molecular programming of TH2 driven pulmonary allergic inflammation. Through these two aims, we will further define the mechanisms by which the let-7bc cluster controls the expression of allergic airway disease, providing novel diagnostic and therapeutic insight into asthma and related disorders.

我们实验室的长期目标是了解 慢性过敏性气道炎症或哮喘，以改善治疗方法。的具体目标 该应用是剖析树突细胞（DC）中的微小RNA（miRNA）依赖性炎症通路， 调节小鼠对真菌过敏原的过敏性气道疾病的CD 4 + T细胞哮喘是一个主要的全球上升 健康威胁，不成比例地影响战斗退伍军人。我们发现哮喘患者通常 呼吸道真菌病的证据，定义为在呼吸道分泌物中检测到真菌， 生物标志物（例如IgE或TH 2细胞）与一种或多种真菌反应。我们的实验室和其他实验室已经证明， 真菌蛋白酶和真菌孢子驱动小鼠的哮喘样气道疾病。气道上皮细胞表达 外来抗原的模式识别受体（PRR）（例如TLR、C型凝集素和蛋白酶激活的 受体），并且对于常规树突状细胞（cDC）活化和过敏性CD 4 + 2型的起始是重要的 细胞（TH 2）和TH 17细胞依赖性气道炎症、IgE产生和气道高反应性 (AHR)统称为过敏性气道疾病。我们和其他人已经证明了TH 2细胞的需求 和DC在过敏性气道疾病发病机制中的作用。我们采用慢性过敏性气道的小鼠模型， 炎症，并检测肺、CD 4 + T细胞和CD 11 c + DC中let-7 miRNA家族的异常表达。 具体地，let-7 b和let-7 c（let-7 bc-簇）的表达在分选的肺CD 4 + T细胞中降低， 在慢性过敏性气道疾病小鼠的CD 11 c+抗原呈递细胞（APC）中增强。此外，委员会认为， 在CD 4 + T细胞或CD 11 c + APC中整体或特异性缺乏let-7 bc-簇的小鼠显示钝化的TH 2 反应和过敏性疾病。另一方面，增强let-7在CD 4 + T细胞中的特异性表达， 增强真菌引起的过敏性呼吸道疾病。let-7 b和let-7 c成员仅占 淋巴细胞和骨髓细胞中let-7总活性表明let-7 bc簇决定基因 表达CD 4 + T细胞和DC，驱动对尼日尔曲霉的过敏性致敏。我们的核心假设 因此指出let-7家族调节过敏性气道疾病的严重程度，并协调 cDC和TH 2应答。我们将通过以下具体目标来解决这个假设：1）阐明 过敏性气道疾病发病机制中let-7 bc-簇的CD 4 + T细胞内在需求。 假设：let-7 bc-簇调节CD 4 + T细胞中的靶基因表达并控制TH 2肺 炎症和过敏性气道疾病。2)确定let-7 bc-簇在DC介导的控制中的作用， 过敏性气道炎症假设：哮喘肺cDC中let-7 bc簇表达的诱导 TH 2驱动的肺变应性炎症的分子编程。通过这两个目标，我们将进一步 确定let-7 bc簇控制过敏性气道疾病表达的机制， 为哮喘和相关疾病提供新的诊断和治疗见解。

项目成果

Alveolar macrophages in lung cancer: opportunities challenges.

• DOI: 10.3389/fimmu.2023.1268939
• 发表时间: 2023
• 期刊: FRONTIERS IN IMMUNOLOGY
• 影响因子: 7.3
• 作者: Chang, Cheng-Yen;Armstrong, Dominique;Corry, David B.;Kheradmand, Farrah
• 通讯作者: Kheradmand, Farrah

Computer-Assisted Analysis of Oral Antifungal Therapy in Chronic Rhinosinusitis with Airway Mycosis: a Retrospective Cohort Analysis.

慢性鼻窦炎伴气道真菌病口服抗真菌治疗的计算机辅助分析：回顾性队列分析。

• DOI: 10.1128/aac.01697-21
• 发表时间: 2021
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Li,Evan;Scheurer,Michael;Kheradmand,Farrah;Luong,AmberU;Corry,DavidB
• 通讯作者: Corry,DavidB

Novel acute hypersensitivity pneumonitis model induced by airway mycosis and high dose lipopolysaccharide.

气道真菌病和大剂量脂多糖诱导的新型急性过敏性肺炎模型

• DOI: 10.1186/s12931-021-01850-5
• 发表时间: 2021-10-10
• 期刊: Respiratory research
• 影响因子: 5.8
• 作者: Zeng Y;Zhang Y;Huang X;Song L;Polsky K;Wu Y;Kheradmand F;Guo Y;Green LK;Corry DB;Knight JM
• 通讯作者: Knight JM

The immune response to airway mycosis.

• DOI: 10.1016/j.mib.2021.04.009
• 发表时间: 2021-08
• 期刊: Current opinion in microbiology
• 影响因子: 5.4
• 作者: Li E;Rodriguez A;Luong AU;Allen D;Knight JM;Kheradmand F;Corry DB
• 通讯作者: Corry DB

Candida albicans elicits protective allergic responses via platelet mediated T helper 2 and T helper 17 cell polarization.

• DOI: 10.1016/j.immuni.2021.08.009
• 发表时间: 2021-11-09
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Wu Y;Zeng Z;Guo Y;Song L;Weatherhead JE;Huang X;Zeng Y;Bimler L;Chang CY;Knight JM;Valladolid C;Sun H;Cruz MA;Hube B;Naglik JR;Luong AU;Kheradmand F;Corry DB
• 通讯作者: Corry DB