HuR in Allergic Asthma and T cell Differentiation

HuR 在过敏性哮喘和 T 细胞分化中的作用

• 批准号: 9590179
• 负责人: ULUS ATASOY
• 金额: $ 17.7万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-14 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9590179
• 关键词: Ablation; Adoptive Transfer; Affect; Agonist; Allergens; Allergic; Asthma; Binding; CD4 Positive T Lymphocytes; Cellular biology; Cytokine Gene; Development; Disease; Distal; Elements; Extrinsic asthma; Functional disorder; Funding; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Goals; Heterogeneity; Homeostasis; Human; Hypersensitivity; Immunoprecipitation; In Vitro; Incidence; Inflammation; Inflammatory Response; Interleukin-2; Knockout Mice; Knowledge; Lung; Lung Inflammation; Lung diseases; Lymphocyte; Mediating; Messenger RNA; Methods; MicroRNAs; Mission; Molecular; Morbidity - disease rate; Natural Immunity; Outcome; Ovum; Patients; Peripheral Blood Lymphocyte; Pharmaceutical Preparations; Play; Process; Production; Proteins; Public Health; Pulmonary Inflammation; Pyroglyphidae; RNA; RNA-Binding Proteins; Regulation; Research; Role; Small Interfering RNA; Steroids; System; T cell differentiation; T-Cell Activation; T-Lymphocyte; Testing; Trans-Activators; Transgenic Mice; Transgenic Model; United States National Institutes of Health; Untranslated Regions; Work; adaptive immunity; airway inflammation; allergic airway inflammation; cell type; cytokine; disease heterogeneity; experience; genome-wide; in vivo; innovation; insight; knock-down; mortality; novel; permissiveness; public health relevance; response; transcriptomics

DESCRIPTION (provided by applicant): For unknown reasons, the incidence of allergies and asthma continues to increase in the US. It is increasingly clear that asthma is a heterogeneous disease with differing endotypes which suggest discrete pathophysiology. In humans, asthma exists in allergic and non-allergic forms. It is an unmet need in the field to better understand ho different mechanisms contribute to asthma endotypes. Genome wide array analysis has identified many asthma relevant genes. However, due to poor correlation between steady state mRNA levels and protein, transcriptomic approaches may overlook critical genes. Posttranscriptional gene regulation by RNA binding proteins (RBPs) and microRNAs (miRNAs) are increasingly recognized as important control mechanisms for proinflammatory genes. RBPs, such as HuR (elav1) which bind to AU-rich elements (AREs) play critical roles in coordinately regulating proinflammatory genes in asthma by stabilizing target gene mRNAs and increasing translatability. Methods used by our lab and others, called RNA immunoprecipitation applied to microarrays (RIP-Chip) have identified how RBPs are coordinately regulating inflammation. Posttranscriptional gene regulation plays an important role in CD4+ T differentiation, yet these processes are poorly understood. Our long term goal is to understand posttranscriptional gene regulation in airway inflammation. The objective of this application, which is our next step in pursuit of that goal, is to understand how HuR is regulating key molecules, such as Th2/Th17 cytokines and IL-2 during allergen challenge. The central esis is that the RBP, HuR, is permissive for development of CD4+ Th2 mediated allergic airway inflammation and required for normal IL-2 homeostatic expression. The rationale for this proposal is that our work has demonstrated that HuR controls both Th2 and Th17 differentiation. HuR KO mice do not develop airway inflammation due to suppression of Th2 cytokine production and do not have the ability to turn off IL-2 expression following T cell activation. Understanding posttranscriptional mechanisms of IL-2 and Th2/Th17 cytokine gene regulation will allow the field to modulate and affect outcomes of inflammatory responses in allergen driven asthma and also perhaps aid in better defining the heterogeneity amongst asthma endotypes. We plan to test the central esis and accomplish these objectives by the following four specific aims: 1) Does HuR ablation alter CD4+ Th subset differentiation?; 2) Determine whether HuR is required for allergic airway inflammation in vivo; 3) Mechanistic determinants of IL-2 and Th2 cytokine expression; 4) Determine whether human lymphocytes have dysregulated HuR expression. We believe our study is innovative, because such approaches will provide novel mechanistic insights into T cell posttranscriptional cytokine regulation. The proposed research is significant, because it will elucidate how airway responses connect at the molecular level with both adaptive and innate immunity to control lung inflammation.

描述（由申请人提供）：由于未知的原因，美国过敏和哮喘的发病率持续增加。越来越清楚的是，哮喘是一种异质性疾病，具有不同的内型，这表明其病理生理学是离散的。在人类中，哮喘以过敏性和非过敏性形式存在。更好地了解不同机制如何导致哮喘内型是该领域未满足的需求。全基因组分析已鉴定出许多哮喘相关基因。然而，由于稳态 mRNA 水平和蛋白质之间的相关性较差，转录组学方法可能会忽略关键基因。 RNA 结合蛋白 (RBP) 和 microRNA (miRNA) 的转录后基因调控越来越被认为是促炎基因的重要控制机制。 RBP，例如与富含 AU 的元件 (ARE) 结合的 HuR (elav1)，通过稳定靶基因 mRNA 和增加可翻译性，在协调调节哮喘促炎基因方面发挥着关键作用。我们的实验室和其他实验室使用的方法（称为应用于微阵列的 RNA 免疫沉淀法 (RIP-Chip)）已经确定了 RBP 如何协调调节炎症。转录后基因调控在 CD4+ T 分化中发挥着重要作用，但人们对这些过程知之甚少。我们的长期目标是了解气道炎症中的转录后基因调控。该应用程序的目的是了解 HuR 在过敏原挑战过程中如何调节关键分子，例如 Th2/Th17 细胞因子和 IL-2，这是我们追求这一目标的下一步。核心观点是，RBP、HuR 允许 CD4+ Th2 介导的过敏性气道炎症的发生，并且是正常 IL-2 稳态表达所必需的。该提议的基本原理是我们的工作已经证明 HuR 控制 Th2 和 Th17 分化。 HuR KO 小鼠不会因 Th2 细胞因子产生的抑制而发生气道炎症，并且不具备在 T 细胞激活后关闭 IL-2 表达的能力。了解 IL-2 和 Th2/Th17 细胞因子基因调控的转录后机制将使该领域能够调节和影响过敏原驱动的哮喘中炎症反应的结果，并且可能有助于更好地定义哮喘内型之间的异质性。我们计划测试中心 esis 并通过以下四个具体目标来实现这些目标：1）HuR 消融是否会改变 CD4+ Th 子集分化？ 2）确定体内过敏性气道炎症是否需要HuR； 3）IL-2和Th2细胞因子表达的机制决定因素； 4) 确定人淋巴细胞是否存在HuR表达失调。我们相信我们的研究具有创新性，因为此类方法将为 T 细胞转录后细胞因子调节提供新的机制见解。拟议的研究意义重大，因为它将阐明气道反应如何在分子水平上与适应性和先天免疫联系起来以控制肺部炎症。