HuR in Allergic Asthma

过敏性哮喘中的 HuR

• 批准号: 7729032
• 负责人: ULUS ATASOY
• 金额: $ 28.33万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7729032
• 关键词: 3' Untranslated Regions; Affect; Allergens; Allergic; Animal Model; Animals; Area; Asthma; Binding; Biological; Biological Assay; CD4 Positive T Lymphocytes; Cell Nucleus; Cloning; Complex; Cytokine Gene; Cytoplasm; Data; Development; Disabled Persons; Disease; ERG gene; Elements; Employee Strikes; Extrinsic asthma; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Goals; Hypersensitivity; IL13 gene; Immunoprecipitation; Incidence; Indium; Inflammation; Inflammatory; Inflammatory Response; Interleukin-13; Interleukin-4; Interleukin-5; Knock-out; Lead; Lentivirus Vector; Lung; Lymphocyte; Mediating; Messenger RNA; MicroRNAs; Modality; Modeling; Mus; Operon; Outcome; Ovalbumin; Ovum; Pathogenesis; Phenotype; Play; Prevalence; Production; Proteins; Public Health; Publishing; RNA-Binding Proteins; Regulation; Reporting; Research; Research Personnel; Role; Severities; T-Cell Activation; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Translations; Up-Regulation; Work; allergic airway inflammation; base; cDNA Arrays; chemokine; cytokine; design; experience; gain of function; handicapping condition; in vivo; innovation; loss of function; novel strategies; public health relevance; response

DESCRIPTION (provided by applicant): Asthma has been increasing in prevalence and severity for unknown reasons. Though our understanding of the pathophysiology remains poor, it is widely accepted that asthma is an inflammatory disease and CD4+ T cells elaborating Th2 cytokines have been identified as major culprits in its development. Many of these genes are posttranscriptionally regulated but their regulation is not well understood. We have developed a new paradigm, the posttranscriptional operon hypothesis, which states that RNA binding proteins are coordinately regulating the expression of biologically related molecules. Our hypothesis is that the RNA binding protein, HuR, is coordinately regulating Th2 polarization and cytokine gene expression in allergic airway inflammation. HuR is a major stabilizer of labile mRNAs containing AU rich instability elements (AREs) in their 3' untranslated regions. All the Th2 cytokines and 90% of cytokines and chemokines have AREs. 1. Determine effects of HuR modulation upon Th2 polarization and cytokine production in lymphocytes. We will employ lentiviral vectors to under-express HuR in CD4+ T cells and assay Th1/Th2 polarization and cytokine gene expression. 2. Determine role of HuR over-expression and under-expression in murine models of allergic airway inflammation. We will test whether altering HuR levels will modify asthma development in animal models of allergic airway inflammation. 3. Does HuR mediated allergic inflammation involves microRNAs? We will isolate and identify microRNAs from lungs of ova sensitized animals using arrays. Our approach will provide a fuller understanding of the identity and regulation of proinflammatory genes involved in asthma. Better understanding of proinflammatory gene regulation at the posttranscriptional level may potentially lead to targeted therapies to treat asthma. PUBLIC HEALTH RELEVANCE: The reasons for the increasing incidence and prevalence of allergies and asthma worldwide are presently unknown. Exciting new discoveries in posttranscriptional gene regulation and microRNAs potentially may have broad impacts on our understanding of allergen driven asthma. The aim of this proposal is to better understand how cytokine genes are regulated at the posttranscriptional level. This would greatly aid in our understanding of disease pathogenesis and treatment and have a direct impact on public health. PHS 398/2590 (Rev. 09/04) Page 15 Continuation Format Page

描述（由申请人提供）：由于未知的原因，哮喘的患病率和严重程度不断增加。尽管我们对病理生理学的了解仍然很少，但人们普遍认为哮喘是一种炎症性疾病，而产生 Th2 细胞因子的 CD4+ T 细胞已被确定为其发展的主要罪魁祸首。许多这些基因受到转录后调节，但它们的调节尚不清楚。我们开发了一种新的范式，即转录后操纵子假说，该假说指出 RNA 结合蛋白协调调节生物相关分子的表达。我们的假设是，RNA 结合蛋白 HuR 协调调节过敏性气道炎症中的 Th2 极化和细胞因子基因表达。 HuR 是不稳定 mRNA 的主要稳定剂，其 3' 非翻译区含有 AU 丰富的不稳定元件 (ARE)。所有 Th2 细胞因子以及 90% 的细胞因子和趋化因子都含有 ARE。 1. 确定 HuR 调节对淋巴细胞中 Th2 极化和细胞因子产生的影响。我们将采用慢病毒载体在 CD4+ T 细胞中低表达 HuR，并测定 Th1/Th2 极化和细胞因子基因表达。 2.确定HuR过表达和低表达在过敏性气道炎症小鼠模型中的作用。我们将测试改变 HuR 水平是否会改变过敏性气道炎症动物模型中的哮喘发展。 3. HuR介导的过敏性炎症是否涉及microRNA？我们将使用阵列从卵致敏动物的肺部分离和鉴定 microRNA。我们的方法将提供对哮喘相关促炎基因的识别和调节的更全面的了解。更好地了解转录后水平的促炎基因调控可能会导致治疗哮喘的靶向疗法。公共卫生相关性：全球过敏和哮喘发病率和患病率不断增加的原因目前尚不清楚。转录后基因调控和 microRNA 方面令人兴奋的新发现可能会对我们对过敏原驱动的哮喘的理解产生广泛影响。该提案的目的是更好地了解细胞因子基因如何在转录后水平受到调节。这将极大地帮助我们了解疾病的发病机制和治疗，并对公共卫生产生直接影响。 PHS 398/2590 (Rev. 09/04) 第 15 页 继续格式页