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

基本信息

批准号：
9021588
负责人：
ULUS ATASOY
金额：
$ 54.47万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
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/9021588
关键词：
Ablation Adoptive Transfer Affect Agonist Allergens Allergic Asthma Binding Cellular biology Cytokine Gene Development Disease Distal Elements Extrinsic asthma Functional disorder Funding Gene Expression Gene Expression Regulation Gene Targeting Genes Goals Health 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 Steroid therapy System T cell differentiation T-Cell Activation T-Lymphocyte Testing Trans-Activators Transgenic Mice Transgenic Model 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 response transcriptomics

项目摘要

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）：由于未知原因，美国过敏和哮喘的发生率在美国继续增加。越来越明显的是，哮喘是一种异质性疾病，具有不同的内型，这表明了离散的病理生理学。在人类中，哮喘以过敏和非过敏性形式存在。在该领域，这是一种未满足的需求，以更好地了解HO的不同机制有助于哮喘内型。基因组广泛的阵列分析已经确定了许多哮喘相关基因。但是，由于稳态mRNA水平和蛋白质之间的相关性差，转录组方法可能会忽略关键基因。 RNA结合蛋白（RBP）和microRNA（miRNA）的转录后基因调节越来越被认为是促炎基因的重要控制机制。 RBP，例如HUR（ELAV1）与富含AU的元素（ARES）结合，通过稳定靶基因mRNA和增加可翻译性，在协同调节哮喘中的促炎基因中起关键作用。我们的实验室和其他方法（称为RNA免疫沉淀应用于微阵列（RIP-CHIP））的方法已经确定了RBP如何协调调节炎症。转录后基因调控在CD4+ T分化中起着重要作用，但这些过程却鲜为人知。我们的长期目标是了解气道炎症中的转录后基因调节。该应用的目的是我们追求该目标的下一步，是要了解HUR如何调节关键分子，例如TH2/TH17细胞因子和在过敏原挑战期间IL-2。中央ESI是RBP HUR允许开发CD4+ TH2介导的过敏性气道炎症，并且需要正常的IL-2稳态表达。该提议的理由是我们的工作表明HUR控制TH2和TH17的分化。由于Th2细胞因子产生的抑制，HUR KO小鼠不会出现气道炎症，并且在T细胞激活后无法关闭IL-2表达。了解IL-2和TH2/TH2/TH17细胞因子基因调节的转录后机制将使该领域能够调节和影响过敏原驱动哮喘的炎症反应的结果，并可能有助于更好地定义哮喘内部型哮喘内型的异质性。我们计划通过以下四个特定目的来测试中央ESI并实现这些目标：1）HUR消融会改变CD4+ TH子集分化吗？ 2）确定体内过敏性气道炎症是否需要HUR； 3）IL-2和Th2细胞因子表达的机械决定因素； 4）确定人类淋巴细胞的HUR表达失调。我们认为我们的研究具有创新性，因为这种方法将为转录后细胞因子调节提供新的机械见解。拟议的研究很重要，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相连接以控制肺部炎症。